Polymerization method from the combinatorial synthesis and analysis of organometallic compounds and catalysts

ABSTRACT

The present invention relates, inter alia, to methodologies for the synthesis, screening and characterization of organometallic compounds and catalysts (e.g., homogeneous catalysts). The methods of the present invention provide for the combinatorial synthesis, screening and characterization of libraries of supported and unsupported organometallic compounds and catalysts (e.g., homogeneous catalysts). The methods of the present invention can be applied to the preparation and screening of large numbers of organometallic compounds which can be used not only as catalysts (e.g., homogeneous catalysts), but also as additives and therapeutic agents.

This application is a Divisional of Ser. No. 08/898,715 filed (Jul. 22,1997) now U.S. Pat. No. 6,030,917 which is a continuation-in-part ofSerial No. 60/048,987, filed Jun. 9, 1997, which is acontinuation-in-part of Serial No. 60/035,366, filed on Jan. 10, 1997,which is a continuation-in-part of Serial No. 60/029,255, filed on Oct.25, 1996, which is a continuation-in-part of Serial No. 60/028,106,filed on Oct. 9, 1996, which is a continuation-in-part of Serial No.60/016,102, filed on Jul. 23, 1996, the teachings of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates, inter alia, to methodologies for thesynthesis, screening and characterization of organometallic compoundsand catalysts. The methods of the present invention provide for thecombinatorial synthesis, screening and characterization of libraries ofsupported and unsupported organometallic compounds and catalysts. Themethods of the present invention can be applied to the preparation andscreening of large numbers of organometallic compounds which can be usednot only as catalysts (e.g., homogeneous catalysts), but also asadditives and therapeutic agents.

BACKGROUND OF THE INVENTION

Ancillary ligand-stabilized metal complexes (i.e., organometalliccomplexes) are useful as catalysts, additives, stoichiometric reagents,monomers, solid state precursors, therapeutic reagents and drugs. Theancillary ligand system comprises organic substituents, bind to themetal center(s), remain associated with the metal center(s), andtherefore provide an opportunity to modify the shape, electronic andchemical properties of the active metal center(s) of the organometalliccomplex.

Certain organometallic complexes are catalysts for reactions such asoxidation, reduction, hydrogenation, hydrosilylation, hydrocyanation,hydroformylation, polymerization, carbonylation, isomerization,metathesis, carbon-hydrogen activation, cross coupling, Friedel-Craftsacylation and alkylation, hydration, dimerization, trimerization andDiels-Alder reactions. Organometallic complexes can be prepared bycombining an ancillary ligand precursor with a suitable metal precursorin a suitable solvent at a suitable temperature. The yield ACTIVITY ANDSELECTIVITY of the targeted organometallic complex is dependent on avariety of factors including the form of the ancillary ligand precursor,the choice of the metal precursor, the reaction conditions (e.g.,solvent, temperature, time, etc.) and the stability of the desiredproduct. In some cases, the resulting organometallic complex is inactiveas a catalyst until it is “activated” by a third component orcocatalyst. In many cases, third component “modifiers” are added toactive catalysts to improve performance. The effectiveness of thecocatalyst, the type and amount of modifier, and the suitability of theancillary ligand precursor, metal precursor and reaction conditions toform an effective catalyst species in high yield are unpredictable fromfirst principles. Given the number of variables involved and the lack oftheoretical capability, it is not surprising that the discovery andoptimization of catalysts is laborious and inefficient.

One important example of this is the field of single-sited olefinpolymerization catalysis. The active site typically comprises anancillary ligand-stabilized coordinatively unsaturated transition metalalkyl complex. Such catalysts are often prepared by the reaction of twocomponents. The first component is an ancillary ligand-stabilizedtransition metal complex having a relatively low coordination number(typically between three and four). The second component, known as theactivator or cocatalyst, is either an alkylating agent, a Lewis acidcapable of abstracting a negatively charged leaving group ligand fromthe first component, an ion-exchange reagent comprising a compatiblenon-coordinating anion or a combination thereof. Although a variety oforganometallic catalysts have been discovered over the past 15 years,this discovery is a laborious process which consists of synthesizingindividual potentially catalytic materials and subsequently screeningthem for catalytic activity. The development of a more efficient,economical and systematic approach for the synthesis of novelorganometallic catalysts and for the screening of such catalysts foruseful properties would represent a significant advance over the currentstate of the art. A particularly promising method for simplifying thediscovery process would rely on methods of producing combinatoriallibraries of ligands and catalysts and screening the compounds withinthose libraries for catalytic activity using an efficient parallel orrapid serial detection method.

The techniques of combinatorial synthesis of libraries of organiccompounds are well known. For example, Pirrung, et al. developed atechnique for generating arrays of peptides and other molecules using,for example, light-directed, spatially-addressable synthesis techniques(U.S. Pat. No. 5,143,854 and PCT Publication No. WO 90/15070). Inaddition, Fodor, et al. have developed automated techniques forperforming light-directed, spatially-addressable synthesis techniques,photosensitive protecting groups, masking techniques and methods forgathering fluorescence intensity data (Fodor, et al., PCT PublicationNo. WO 92/10092). In addition, Ellman, et al. recently developed amethodology for the combinatorial synthesis and screening of librariesof derivatives of three therapeutically important classes of organiccompounds, benzodiazepines, prostaglandins and β-turn mimetics (see,U.S. Pat. No. 5,288,514).

Using these various methods of combinatorial synthesis, arrayscontaining thousands or millions of different organic elements can beformed (U.S. patent application Ser. No. 805,727, filed Dec. 6, 1991).The solid phase synthesis techniques currently being used to preparesuch libraries involve a stepwise process (i.e., sequential, coupling ofbuilding blocks to form the compounds of interest). In the Pirrung, etal. method, for example, polypeptide arrays are synthesized on asubstrate by attaching photoremovable groups to the surface of thesubstrate, exposing selected regions of the substrate to light toactivate those regions, attaching an amino acid monomer with aphotoremovable group to the activated region, and repeating the steps ofactivation and attachment until polypeptides of the desired length andsequences are synthesized. The Pirrung, et al. method is a sequential,step-wise process utilizing attachment, masking, deprotecting,attachment, etc. Such techniques have been used to generate libraries ofbiological polymers and small organic molecules to screen for theirability to specifically bind and block biological receptors (i.e.,protein, DNA, etc.). These solid phase synthesis techniques, whichinvolve the sequential addition of building blocks (i.e., monomers,amino acids) to form the compounds of interest, cannot readily be usedto prepare many inorganic and organic compounds. As a result of theirrelationship to semiconductor fabrication techniques, these methods havecome to be referred to as “Very Large Scale Immobilized PolymerSynthesis,” or “VLSIPS” technology.

Schultz, et al. was the first to apply combinatorial chemistrytechniques to the field of material science (PCT WO/9611878, theteachings of which are incorporated herein by reference). Moreparticularly, Schultz, et al. discloses methods and apparatus for thepreparation and use of a substrate having thereon an array of diversematerials in predefined regions. An appropriate array of materials isgenerally prepared by delivering components of materials to predefinedregions on the substrate and simultaneously reacting the reactants toform different materials. Using the methodology of Schultz, et al., manyclasses of materials can be generated combinatorially including, forexample, inorganic materials, intermetallic materials, metal alloys,ceramic materials, etc. Once prepared, such materials can be screenedfor useful properties. Liu and Ellman, J. Org. Chem. 1995, 60:7, workingin the area of asymmetric catalysis, have developed a solid-phasesynthesis strategy for the 2-pyrrolidinemethanol ligand class, and havedemonstrated that the ligands can be directly evaluated forenantioselective additions of diethyl zinc reagent to aldehydesubstrates using conventional analytical methods and not rapid parallelor serial screening methods.

From the above, it is apparent that there is a need for the developmentof methods for synthesizing and screening libraries of organometallicmaterials for catalytic properties. These methods would greatlyaccelerate the rate discovering and optimizing catalytic process. Quitesurprisingly, the instant invention provides such methods.

SUMMARY OF THE INVENTION

The present invention relates to methods for the synthesis andcharacterization of arrays, i.e., libraries of catalysts andorganometallic compounds. More particularly, the methods of the presentinvention provide for the combinatorial synthesis, screening andcharacterization of large arrays or libraries of diverse supported andunsupported ligands, catalysts and organometallic compounds.

Thus, in one aspect, the present invention provides a method of makingand screening an array of metal-ligand compounds, the method comprising:

(a) synthesizing a spatially segregated array of ligands;

(b) delivering a suitable metal precursor to each element of the arrayof ligands to create an array of metal-ligand compounds;

(c) optionally activating the array of metal-ligand compounds with asuitable cocatalyst;

(d) optionally modifying the array of metal-ligand compounds with athird component; and

(e) screening the array of metal-ligand compounds for a useful propertyusing a parallel or rapid serial screening technique selected from thegroup consisting of optical imaging, optical spectroscopy, massspectrometry, chromatography, acoustic imaging, acoustic spectroscopy,infrared imaging and infrared spectroscopy.

In yet another aspect, the invention comprises an array of between 10and 10⁶ different metal-ligand compounds at known locations on thesubstrate. In certain embodiments, the array will comprise more than 50different metal-ligand compounds at known locations on the substrate. Inother embodiments, the array will comprise more than 100 or more than500 different metal-ligand compounds. In still further embodiments, thearray will comprise more than 1,000, more than 10,000 or more than 10⁶different metal-ligand compounds at known locations on the substrate.

Other features, objects and advantages of the invention and itspreferred embodiments will become apparent from the detailed descriptionwhich follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B illustrate examples of transition-metal basedmetallocene catalysts and catalysts based on the late transition metals,e.g., zirconium and nickel, respectively.

FIGS. 2A and 2B illustrate sequences of solid-phase reactions which canbe used to achieve combinatorial variations of diimine and/or diamineligands.

FIGS. 3A and 3B illustrate various combinatorial routes for thesynthesis of various ligand types.

FIGS. 4A-4G illustrate examples of ligand cores which can be made usingcombinatorial chemistry formats.

FIG. 5 illustrates a synthesis of an exemplary ancillary ligand on asupport, wherein CN=1 or 2, charge=0 or −1.

FIG. 6 illustrates a synthesis of an exemplary ancillary ligand on asupport, wherein CN=1, 2 or 3, charge=0, −1 or −2.

FIG. 7 illustrates a synthesis of an exemplary ancillary ligand withmetal complex on a support, wherein CN=2, charge=−2, denoted [2,2].

FIG. 8 illustrates the synthesis of two exemplary ancillary ligands offsupport, wherein CN=2, charge =0, −1 or −2.

FIG. 9 illustrates a synthesis of an exemplary ancillary ligand offsupport, wherein CN=2, charge=−1, denoted [2,1].

FIG. 10 illustrates a synthesis of an exemplary ancillary ligand offsupport with a functional linker, wherein CN=2, charge=0, −1, −2 or −3.

FIG. 11 illustrates a synthesis of an exemplary ancillary ligand offsupport with a “functionless” linker, wherein CN=2, charge=0, −1 or −2.

FIG. 12 illustrates a synthesis of an exemplary ancillary ligand offsupport wherein CN=2 or 3, charge=0, −1, −2, −3 or −4.

FIGS. 13A and 13B illustrate exemplary synthetic schemes useful in theplacement of acidic functionality on the R-group substituents within thearray or library.

FIGS. 14A and 14B illustrate various exemplary substrate configurationswhich can be used in carrying out the methods of the present invention.

FIG. 15 illustrates an example of a system employing a differentiallypumped mass spectrometer that samples product stream or volumesurrounding the library compound.

FIG. 16 illustrates an example of an individual flow-through librarysystem.

FIG. 17 illustrates an example of a Supersonic Molecular Beam SamplingSystem.

FIG. 18 illustrates an example of a system employing a single stagedifferentially pumped mass spectrometer.

FIG. 19 illustrates an example of a differentially pumped massspectrometer with a simplified flow system.

FIGS. 20 and 21 illustrates systems employing ultraviolet and visibleemission-excitation spectroscopy.

FIG. 22 illustrates a system employing infrared absorption.

FIG. 23 illustrates a system employing an infrared imaging camera tomeasure infrared emissions.

FIG. 24 illustrates a system for detecting photon scattering.

FIG. 25 illustrates a system for ultrasonic monitoring.

FIG. 26 illustrates a system using a PZT pads which are attached to ordeposited directly under the individual library elements.

FIG. 27 illustrates the synthesis of a library of 48 diimine ligandswhich is subsequently converted to a library of 96 diimine-metalcompounds.

FIG. 28 illustrates a generalized solution-phase synthesis of diiminesutilizing immobilized catalysts, proton sponges and reactant adsorbingreagents.

FIG. 29 illustrates an array of commercially-available diketones of usein practicing the present invention.

FIG. 30 illustrates examples of immobilized Lewis acid catalysts anddehydrating reagents.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS TABLE OFCONTENTS

I. Glossary: Abbreviations and Definitions

II. Assembly of Combinatorial Libraries

A. General Overview

B. Synthesis Supports and Substrates

C. Ligands

D. Linkers

E. Metals

F. Immobilized Reagents

G. Non-coordinating Anions (NCA)

H. Diimine Catalyst Library Design and Synthesis

III. Screening of Combinatorial Libraries

A. Introduction

B. Identification and Characterization of Gas Phase Products or VolatileComponents of the Condensed Phase Products

1. Gas Phase Characterization by Mass Spectroscopy

(i) Differentially Pumped Mass Spectrometer that Samples Product Streamor Volume Surrounding the Library Compound

(ii) Supersonic Molecular Beam Sampling System

(iii) Single Stage Differentially Pumped Mass Spectrometer

(iv) Individual Flow-Through Library Sampling

(v) Differentially Pumped Mass Spectrometer with a Simplified FlowSystem

(vi) Embedded Catalyst Impregnated in Micro-porous Silica Capped byMacro-porous Silica

2. Gas Phase Characterization by Optical Spectroscopy:

(i) Ultraviolet and Visible Emission- Excitation Spectroscopy

(ii) Scanning Multi-Wave Mixing Fluorescence Imaging

3. Gas Phase Characterization by Gas Chromatography:

(i) Gas Chromatography

C. Characterization of Condensed Phase Products

1. Condensed Phase Product Characterization by Optical Methods

(i) Infrared Absorption

(ii) Photon Scattering Analysis

(iii) Polarized Light Imaging

2. Condensed Phase Product Characterization by Mechanical Properties

(i) Ultrasonic Monitoring

D. Measurement of Physical Properties of the Catalyst Library

1. Characterization by Heat of Reaction

(i) Two-dimensional Infrared Imaging for Parallel Monitoring of CatalystLibrary Heat of Reaction

IV. EXAMPLES

I. Glossary: Abbreviations and Definitions

Abbreviations and generalized chemical formulae used herein have thefollowing meanings: Cp, {acute over (η)}5-cyclopentadienyl; Cp*, {acuteover (η)}5-pentamethylcyclopentadienyl; MAO, methylaluminaoxane;[Q]⁺[NCA]⁻, reactive cation/non-coordinating anion compound; EDG,electron-donating group; EWG, electron-withdrawing group; DME,dimethoxyethane; PEG, poly(ethyleneglycol); DEAD,diethylazodicarboxylate; COD, cyclooctadiene; DBU,1,8-diazabicyclo[5.4.0]undec-7-ene; FMOC, 9-fluorenylmethoxycarbonyl;HOBT, 1-hydroxybenzotriazole; BTU,O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate; DIAD,diisopropylazodicarboxylate. Other abbreviations and chemical formulaeused herein have the meaning normally assigned to them by those of skillin the art.

Catalyst: As used herein, the term “catalyst” refers to a compound whichspeeds a chemical reaction or causes it to occur. The catalysts of thepresent invention are formally organometallic compounds. Certain of theorganometallic compounds of the invention will require “activation”prior to being catalytically active. Other organometallic compounds ofthe invention will be “activator-free catalysts” and will not requireactivation prior to being catalytically active.

Ligand: Organometallic compounds are conventionally formulated ascomprising a central metal atom or ion surrounded by and bonded to otheratoms, ions, or small molecules known as “ligands”. Ligands are eitherorganic (e.g., η¹-aryl, alkenyl, alkynyl, cyclopentadienyl, CO,alkylidene, carbene) or inorganic (e.g., Br⁻, Cl⁻, OH⁻, NO²⁻, etc.), andcan be charged or neutral. The number of times an inorganic or organicmoiety occurs as a ligand in a metallic complex is generally indicatedby the prefixes di, tri, tetra, etc. Multiple occurrences of complexorganic ligands are indicated by the prefixes bis, tris, tetrakis, etc.

As used herein, the term “ancillary ligand” is distinguished from a“leaving group ligand.” An ancillary ligand will remain associated withthe metal center(s) as an integral constituent of the catalyst ororganometallic compound. Ancillary ligands are defined according to thenumber of coordination sites they occupy and their formal charge. Aleaving group ligand is a ligand which is replaced in a ligandsubstitution reaction. A leaving group ligand can be replaced with anancillary ligand or an activator component.

In most cases, the formalisms for assigning the charge on the ligand andthe number of coordination sites it occupies are easily established andunambiguous. As with most chemical formalisms, there are examples wherethese assignments are subject to interpretation and debate. Such is thecase with the η5 cyclopentadienyl (Cp) ligand which is considered tooccupy 3 or 1 coordination site(s) on the metal, depending on theoverall symmetry about the metal center. When the symmetry of the metalcomplex is best described as octahedral, the Cp-ligand will be assignedto occupy 3-coordination sites (on face of the octahedron). If, however,the metal complex symmetry is best described as tetrahedral, squareplanar or trigonal, the Cp-ligand is considered to occupy 1-coordinationsite. For the purposes of this invention, the Cp-ligand will formally beconsidered to occupy 1-coordination site on the metal complex.

Activator: In general, activators are used in the synthesis of variouscatalysts. Activators render a metallic center active as a catalyst andcan be, for example, a chemical or an energy source which renders ametal center active and which, in certain embodiments, is directed froma source to a catalyst precursor which is located at a defined region ona substrate.

In certain embodiments wherein an activator is a chemical reagent whichconverts a metal complex into an olefin polymerization catalyst, theactivator will generally fall into one of two broad classes of agents:(1) alkylating agents; and (2) ionizing agents.

“Alkylating agents,” as used herein, define agents which function byexchanging unreactive ligands, such as, for example, halide or alkoxide,for reactive σ-bonded alkyl groups, such as, for example, methyl orethyl groups. An example of this type of activation is illustrated bythe conversion of Cp₂*ScCl into Cp₂*ScMe (where Cp*=η₅−C₅Me₅) usingmethyllithium. In general, activation by alkylation works in systemswhere the metal center of the catalyst precursor is highlycoordinatively unsaturated and does not require further reduction ofcoordination number to function as a catalyst; however, this mode ofactivation is not limited to such metal centers.

“Ionizing agents” function as activators by reducing the coordinationnumber of the transition metal precursor by at least one coordinationsite to form ionic products. There are two types of ionizing agents: (1)Lewis acids; and (2) ion-exchange activators.

“Lewis acids” function by abstracting a leaving group ligand from themetal center to form a compatible non-coordinating anion (“NCA” which iscomprised of the leaving group ligand and the Lewis acid) and acoordinatively unsaturated active transition metal cation. “Ion-exchangeactivators” deliver to the catalyst precursor a preformed compatiblenon-coordinating anion and accept from the catalyst precursor acoordinating anion (such as a methyl or halide group). Ion-exchangeactivators have the general formula Q⁺NCA⁻, wherein Q⁺ is a reactivecation and NCA⁻ is a compatible non-coordinating anion. The Lewis acidsand ion exchange activators of use with the present invention includeboth soluble and supported (e.g., silica resin bound) Lewis acids andion exchangers.

In some cases, activation can also be accomplished by Lewis acid orion-exchange agents. For example, consider two possible chemicalpathways leading to the synthesis of the catalyst,[Cp₂ZrCH₃]⁺[B(C₆F₅)₃CH₃]⁻, where [B(C₆F₅)₃CH₃] is the “compatiblenon-coordinating anion” or “counter-ion”. Using the Lewis acid pathway,the catalyst precursor is [Cp₂Zr(CH₃)₂] and the activator is [B(C₆F₅)₃].Using the “ion-exchange” pathway, the catalyst precursor is[Cp₂Zr(CH₃)₂] and the activator is [Ph₃C]⁺[B(C₆F₅)₃CH₃]−. These examplesdemonstrate that all or part of the activator can become the“non-coordinating anion” or “counterion.”

Compatible Non-coordinating Anion: A compatible non-coordinating anionis an anion that either does not coordinate to the metal cation, or isonly weakly coordinated to the metal cation such that it remainssufficiently labile to be displaced by a neutral Lewis base or themolecule being transformed in the catalytic cycle. The term “compatiblenon-coordinating anion” specifically refers to an anion which whenfunctioning as a stabilizing anion in the catalyst system of thisinvention does not transfer an anionic fragment to the metal cation toform inactive neutral products.

Organometallic Compounds: Classically, compounds having bonds betweenone or more metal atoms and one or more carbon atoms of an organic groupare defined as “organometallic compounds”. For the purposes of thisapplication, “organometallic” is defined to include all ancillary ligandstabilized metallic complexes regardless of presence or absence of ametal-carbon bond. As used herein, “organometallic compounds” aredistinguished from catalysts by their lack of useful levels of catalyticactivity in an initial screening. This definition does not, however,preclude a compound which was initially identified as an organometalliccompound without catalytic activity in reference to a certain class ofreactions (e.g., alkene polymerization) but which is later identified ashaving catalytic activity with a different class of reactions (e.g.,alkyne polymerization).

Metallocenes: Organometallic compounds in which a transition metal, suchas, for example, zirconium, cobalt or nickel, is bonded to at least onesubstituted or unsubstituted η5-cyclopentadienyl group.

Substrate: A material having a rigid or semi-rigid surface. In someembodiments, at least one surface of the substrate will be substantiallyflat. In other embodiments, the substrate will be divided intophysically separate synthesis regions. Division of the substrate intophysically separate synthesis regions can be achieved with, for example,dimples, wells, raised regions, etched trenches, or the like. In stillother embodiments, small beads or pellets may be provided on the surfaceby, for example, placing the beads within dimples, wells or within orupon other regions of the substrate's surface. Alternatively, the smallbeads or pellets may themselves be the substrate. An appropriatesubstrate can be made out of any material which is compatible with theprocesses intended to occur thereon. Such materials include, but are notlimited to, organic and inorganic polymers, quartz, glass, silica, etc.The choice of an appropriate substrate for certain given conditions willbe apparent to those of skill in the art.

Synthesis Support: A material such as, for example, silica, alumina, aresin or controlled pore glass (CPG) which is functionalized to allow aligand or a ligand component to be attached either reversibly orirreversibly thereto. Specific examples of synthesis supports includeMerrifield resin and functionalized silica gel. A synthesis support canbe held within or upon a “substrate.” “Synthesis support,” “support,”“bead” and “resin” are used interchangeably herein.

Predefined Region: A predefined region is a localized, addressable areaon a substrate which can be used for formation of a selected materialand is otherwise referred to herein in the alternative as “known”region, “reaction” region, a “selected” region, or simply a “region.”The predefined region may have any convenient shape, e.g., circular,rectangular, elliptical, wedge-shaped, etc. Additionally, the predefinedregion can be a bead or pellet which is coated with a reactantcomponent(s) of interest. In this embodiment, the bead or pellet can beidentified with a tag, such as, for example, an etched binary bar codethat can be used to indicate the history of the bead or pellet (i.e., toidentify which components were deposited thereon). In general, apredefined region is from about 25 cm² to about 10 μm². In a preferredembodiment, a predefined region and, therefore, the area upon which eachdistinct material is synthesized is smaller than about 10 cm². Inanother preferred embodiment, a predefined region is less than 5 cm². Ina further preferred embodiment, a predefined region is less than 1 cm².In yet a further preferred embodiment, a predefined region is less than1 mm² In s till other preferred embodiments, the regions have an arealess than about 10,000 μm². In an additional preferred embodiment, theregions are of a size less than 10 μm².

Linker: As used herein, the term “linker” or “linker arm” refers to amoiety interposed between the substrate and the ligand, catalyst or theorganometallic compound. Linkers are either cleavable or noncleavable.

Metal Ion: As used herein, the term “metal ion” refers to ions which arederived from, for example, simple salts (e.g., AlCl₃, NiCl₂, etc.),complex or mixed salts comprising both organic and inorganic ligands(e.g., [({acute over (η)}5-C₅Me₅)IrCl₂]₂, etc.) and metal complexes(e.g., Gd(NTA)₂, CuEDTA, etc.). Metal ions of use in practicing thepresent invention include, for example, main group metal ions,transition metal ions, lanthanide ions, etc. Zero valent metalprecursors, such as Ni(COD)₂, are included in this definition.

II. Assembly of Combinatorial Libraries

A. General Overview

The present invention provides methods, compositions and devices usedfor the combinatorial synthesis, screening and characterization ofsupported and unsupported organometallic compounds and ancillaryligand-stabilized catalysts (e.g., homogeneous and heterogenouscatalysts) and libraries thereof. Preferably, the synthesis andscreening of such libraries is carried out in a spatially selective,simultaneous, parallel or rapid serial fashion. In the embodimentwherein the library synthesis is carried out in parallel, a parallelreactor is preferably employed. The illustrations herein provide thefirst methods for generating and screening combinatorial libraries oforganometallic compounds and catalysts.

The methods of the present invention provide for the assembly oflibraries of organometallic compounds and catalysts. The catalysts ofthe present invention are either of a type which requires activation byan activating agent or, alternatively, they are activator-freecatalysts. The invention also provides methods for the synthesis of bothsupported and unsupported organometallic compounds and catalysts. Whenthe library compounds are supported, they are either attached to asubstrate or, alternatively, to an intermediate synthesis support whichis itself optionally on or within a substrate. Supported librarycompounds are bound to the substrate or synthesis support eitherdirectly through a functional group attached to a ligand core or,alternatively, through a linker arm which is itself a ligand core orpendent from a ligand core. When the library comprises catalysts, thelibrary can be assembled such that the catalysts are homogeneous,heterogenous or a mixture thereof.

Thus, in one aspect the present invention provides a method of making anarray of metal-ligand compounds, the method comprising:

(a) synthesizing a first metal-binding ligand and a second metal-bindingligand on first and second regions of a substrate;

(b) delivering a first metal ion to the first metal-binding ligand and asecond metal ion to the second metal-binding ligand to form first andsecond metal-ligand compounds.

In this embodiment, ligands are assembled on the substrate by thestep-wise delivery of ligand fragments and the reagents necessary tocouple those fragments. Once the ligands are synthesized, they arereacted with metal ions to form metal-ligand compounds.

In another aspect, the invention provides a method for immobilizingintact ligands on a substrate by binding the ligands to reactive groupson the surface of the substrate. Thus, in this aspect, the invention isa method for making an array of metal-ligand compounds, the methodcomprising:

(a) delivering a first metal-binding ligand and a second metal-bindingligand on first and second regions of a substrate;

(b) delivering a first metal ion to the first metal-binding ligand and asecond metal ion to the second metal-binding ligand to form a firstmetal-ligand compound and a second metal ligand compound.

In another embodiment, the metal-ligand compounds thus synthesized arereacted with an activating agent. Preferred activators include, but arenot limited to, Lewis acids, such as B(C₆F₅)₃ and MAO, and ion-exchangereagents of the form [Q]⁺[NCA]⁻, such as [H(OEt)₂]⁺[BAr₄]⁻ and[H(OEt₂)]⁺[B(C₆F₅)₄]⁻. In a still further preferred embodiment, theactivators are independently selected for each member of the library. Inanother preferred embodiment, the activated metal-ligand compoundscomprise olefin polymerization catalysts. In a further preferredembodiment, the catalysts are activator-free catalysts.

In another aspect, the invention provides a method of making andscreening an array of metal-ligand compounds, the method comprising:

(a) synthesizing a spatially segregated array of ligands;

(b) delivering a suitable metal precursor to each element of said arrayof ligands to create an array of metal-ligand compounds;

(c) optionally activating said array of organometallic complexes with anactivator (e.g., a suitable cocatalyst);

(d) optionally modifying said array of metal-ligand compounds with athird component; and

(e) screening said array of metal-ligand compounds for a useful propertyusing a parallel or serial rapid screening technique selected from thegroup consisting of optical imaging, optical spectroscopy, massspectrometry, chromatography, acoustic imaging, acoustical spectroscopy,infrared imaging, and infrared spectroscopy.

Numerous types of ligands are of use in practicing the present invention(see, FIGS. 1-13). In a preferred embodiment, the ligands are neutralbidentate ligands. In another preferred embodiment, the ligands aremonoanionic bidentate ligands. In yet another preferred embodiment, theligands are chelating diimine ligands. In still another preferredembodiment, the ligands are salen ligands. Preferred ligands have acoordination number which is independently selected from the groupconsisting of 1, 2, 3 and 4. These preferred ligands have a charge whichis independently selected from the group consisting of 0, −1, −2, −3 and−4. Certain preferred ligands have a charge which is greater than theircoordination number.

The ligands are either attached directly or through a linker group to asubstrate or a synthesis support or, alternatively, they are insolution. In a preferred embodiment, the ligands are attached directlyto a synthesis support. In another preferred embodiment, the ligands areattached to a synthesis support through a linker group. In a furtherpreferred embodiment, the ligands are attached to a substrate eitherdirectly or through a linker.

Any of the functional groups on the ligands or the linkers, orcomponents of the ligands or the linkers, can be protected to avoidinterference with the coupling reactions. The protection can be achievedby standard methods or variations thereof. A plethora of protectionschemes for most known functional groups are known to and used by thoseof skill in the art. See, for example, Greene, T., et al., PROTECTIVEGROUPS IN ORGANIC SYNTHESIS, Second Ed., John Wiley and Sons, New York,1991, the teachings of which are herein incorporated by reference.

The chemical synthesis steps can be conducted using solid-phase,solution-phase or a combination of solid-phase and solution-phasesynthetic techniques. The ligand, metal, activator, counterion,substrate, synthesis support, linker to the substrate or synthesissupport and additives can be varied as part of the library. The variouselements of the library are typically varied by, for example, theparallel dispensing of reagents to spatially addressable sites or byknown “split-and-pool” combinatorial methodology. Other techniques forassembling combinatorial libraries will be apparent to those of skill inthe art. See, for example, Thompson, L. A., et al., “Synthesis andApplications of Small Molecule Libraries,” Chem. Rev. 1996, 96:555-600,and references therein which are herein incorporated by reference.

Any number of a wide range of metal ions are appropriate for use in thepresent invention. In a preferred embodiment, the metal ions aretransition metal ions. In another preferred embodiment, the metal ionsare ions of Pd, Ni, Pt, Ir, Rh, Co, Cr, Mo and W. When the metal ion isa transition metal ion, in one preferred embodiment, the metal-bindingligands are neutral bidentate ligands and the transition metal ion isstabilized by a labile Lewis base in the metal precursor. In anotherpreferred embodiment, the ligands are monoanionic bidentate ligands andthe transition metal center is stabilized by a labile anionic leavinggroup ligand in the metal precursor. In a still further preferredembodiment, the ligands are [2,2] or [2,1] ligands and each of theligands is contacted with a main group metal alkyl complex such that theligands are in the mono- or di-protic form. A particularly preferredmetal alkyl complex is a trialkylaluminum complex. In a particularlypreferred embodiment, the resulting metal-ligand compounds are usefulfor an organic transformation requiring a Lewis acid site such as, forexample, stereoselective coupling reactions, olefin oligomerizationreactions and olefin polymerization reactions. In yet another preferredembodiment, the aluminum-ligand compounds are further modified with anion-exchange activator to produce an array of ligand-stabilized cationicaluminum compounds. A preferred ion-exchange activator is[PhNMe₂H][B(C₆F₅)₄].

The catalysts prepared using the methods of the invention can be usefulfor catalyzing a wide variety of reactions including, but not limitedto, oxidation, reduction, hydrogenation, hydrosilation, hydrocyanation,polymerizations (e.g., olefins and acetylenes), water gas shift, oxoreaction, carboalkoxylation of olefins, carbonylation reactions (e.g.,of acetylenes and alcohols, etc.), decarbonylation, etc.

As explained in greater detail hereinbelow, following the synthesis ofthe library, the library compounds are screened for a useful property.In a preferred embodiment, the useful property is a property relating toa polymerization reaction. In another preferred embodiment, the usefulproperty is a mechanical property, an optical property, a physicalproperty or a morphological property. In certain preferred embodiments,the useful property is a chemical property such as, for example, thelifetime of the metal-ligand compounds, the stability of these compoundsunder specific reaction conditions, the selectivity of the librarycompounds for a particular reaction, the conversion efficiency of thelibrary compounds in a particular reaction or the activity of thelibrary compounds in a particular reaction. The library can be screenedfor compounds with useful properties using a wide range of techniques.Thus, in one preferred embodiment, the screening is performed by amethod chosen from the group consisting of scanned mass spectrometry,chromatography, ultraviolet imaging, visible imaging, infrared imaging,electromagnetic imaging, ultraviolet spectroscopy, visible spectroscopy,infrared spectroscopy, electromagnetic spectroscopy and acousticmethods.

In general, the analysis of catalysts and organometallic compoundsrequires the ability to rapidly characterize each member to identifycompounds with specific, desired properties. An exemplary use of thepresent invention is in the discovery and optimization of new catalysts.In a preferred embodiment wherein catalysts are synthesized, theconstituents of the combinatorial library will be analyzed using highthroughput methods for measuring such properties as activity (i.e.,turnover), selectivity in converting reactants into desired products,and stability during operation under a wide variety of substrateconcentrations and reaction conditions. Spatially selectivecharacterization methods include, for example, those capable of: (i)identification and characterization of gas phase products and volatilecomponents of the condensed phase products; (ii) identification andcharacterization of condensed phase products; and (iii) measurement ofphysical properties of the catalyst elements on the library. Similarhigh throughput methodologies can be used for measuring properties otherthan catalysis (e.g., target binding, solubility, hydrophilicity, etc.)of libraries of both organometallic compounds and catalysts.

In yet another aspect, the invention comprises an array of between 10and 10⁶ different metal-ligand compounds at known locations on thesubstrate. In certain embodiments, the array will comprise more than 50different metal-ligand compounds at known locations on the substrate. Inother embodiments, the array will comprise more than 100 or more than500 different metal-ligand compounds. In still further embodiments, thearray will comprise more than 1,000, more than 10,000 or more than 10⁶different metal-ligand compounds at known locations on the substrate.

The assembly of combinatorial libraries of organometallic compounds andcatalysts allows the rapid assessment of the effects of changes innumerous characteristics of the compounds themselves, the reactions usedto prepare the compounds and the reactions in which the compounds takepart. Examples of characteristics and properties (together referred toherein as “parameters”) which can be modified include, but are notlimited to, the identity of the ligand core itself, substituents on theligand core, identity and/or charge of the metal ion, counterion,activator, reaction conditions, solvents, additives, supports,substrates and linkers. Other parameters of interest whose effects canbe investigated by the use of the methods of the present invention willbe apparent to those of skill in the art.

In a preferred embodiment of the present invention, only one parameteris varied per addressable location. In another preferred embodiment, thecompounds synthesized are catalysts and variations in the variousparameters are used to identify optimal species and conditions forcatalyzing, or otherwise carrying out, a desired reaction or class ofreactions.

Combinatorial libraries can be used in the synthesis of bothorganometallic compounds and catalysts to identify the optimal metalion, metal ion charge, geometry and/or coordination number for achievinga property of interest. Similarly, the library can be used to measurethe effects of changes in counterions, activators, reaction conditions,solvents and additives. Properties of the library constituents which areof interest include, for example, catalytic parameters, solubility,conductivity, hydrophilicity, mechanical properties and generalpharmacological parameters (e.g., target binding, pharmacokinetics,distribution volume, clearance, etc.).

A specific example of a type of compound which can be synthesized andanalyzed in a combinatorial format are the diimine Ni and Pd complexesdiscovered by Brookhart. This family of catalysts comprises 1,2 diimineligand moieties bound to either 4-coordinate Ni²⁺ or Pd²⁺ centers. Theseprecursors are then activated with a Lewis acid, such as MAO, andion-exchange reagents of the form [Q]⁺[NCA]⁻, such as [H(OEt)₂]⁺[BAr₄]⁻and [H(OEt₂)]⁺[B(C₆F₅)₄]−, etc., to form polymerization catalysts. Theproperties of the catalyst (e.g., polymer molecular weight capability,polymer branching statistics, etc.) are dependent upon the choice of theconstituents of the catalyst. The use of combinatorial libraries allowsfor the optimization of the nature of these constituents.

Combinatorial libraries can also be used to identify the optimal meansof attaching an organometallic compound or a catalyst to a substrate orsupport (silicate, aluminate, polystyrene, etc.). The catalysts ororganometallic compounds are attached to the substrate or synthesissupport directly through a functional group on a ligand or,alternatively, through a linker arm. Linker arm parameters which can bevaried over a library include, for example, length, charge, solubility,conformational lability and chemical composition. Substituents of theselinkers can be varied and particular combinations of catalysts, linkers,synthesis supports, metals, polymerization conditions, etc. can then beassayed directly for optimal catalytic activity and process operabilityusing a two-dimensional or three-dimensional array format or with beadsupports.

Optimization of compound constituents such as the metal ion, counterion,activator identity and concentration, etc. is accomplished by varyingthe identity or concentration of the constituent whose effect on thecompound produced is being examined. Typically, the parameter will bevaried over the array of addressable locations comprising the library.In addition to the above-described constituents, the nature of thesubstrate can also be varied using a combinatorial strategy.

The effect(s) of altering the characteristics of the constituents of acombinatorial library can be analyzed either directly or indirectly.Thus, in one embodiment, the structure or properties of the librarycompounds themselves are studied. In another embodiment, the effect ofthe library compounds on another molecule or system is studied. Forexample, when a library of polymerization catalysts is synthesized, theeffect of variations in constituents over the library can be assessed byanalyzing the polymer products produced using the constituents of thecatalyst library. Such analysis can examine catalyst characteristicsincluding, for example, molecular weight capability, copolymerizationcapability, lifetime, comonomer compatibility, chemical stability, andability to form polymers of differing topology, molecular weightdistribution and/or microstructure. Other means of analyzingcombinatorial libraries will be apparent to those of skill in the art.

The molar ratio of catalyst/cocatalyst employed preferably ranges from1:10,000 to 100:1, more preferably from 1:5000 to 10:1, most preferablyfrom 1:10 to 1:1. In a particularly preferred embodiment of theinvention the cocatalyst can be used in combination with atri(hydrocarbyl)aluminum compound having from 1 to 10 carbons in eachhydrocarbyl group or an oligomeric or polymeric alumoxane. Mixtures ofactivating cocatalysts may also be employed. It is possible to employthese aluminum compounds for their beneficial ability to scavengeimpurities such as oxygen, water, and aldehydes from the polymerizationmixture. Preferred aluminum compounds include trialkyl aluminumcompounds having from 2 to 6 carbons in each alkyl group, especiallythose wherein the alkyl groups are methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, pentyl, neopentyl, or isopentyl, and methylalumoxane,modified methylalumoxane (that is, methylalumoxane modified by reactionwith triisobutyl aluminum) (MMAO) and isobutylalumoxane. The molar ratioof metal-ligand complex to aluminum compound is preferably from 1:10,000to 100:1, more preferably from 1:1000 to 10:1, most preferably from1:500 to 1:1. A most preferred activating cocatalyst comprises both astrong Lewis acid and an alumoxane, especiallytris(pentafluorophenyl)borane and methylalumoxane, modifiedmethylalumoxane, or diisobutylalumoxane.

The catalysts may be used to polymerize ethylenically and/oracetylenically unsaturated monomers having from 2 to 100,000 carbonatoms either alone or in combination. Preferred monomers include theC₂₋₂₀ α-olefins especially ethylene, propylene, isobutylene, 1-butene,1-pentene, 1-hexene, 3-methyl-1-pentene, 4-methyl-1-pentene, 1-octene,1-decene, long chain, macromolecular a-olefins, and mixtures thereof.Other preferred monomers include styrene, C₁₋₄ alkyl substitutedstyrene, tetrafluoroethylene, vinylbenzocyclobutane,ethylidenenorbomene, 1,4-hexadiene, 1,5-hexadiene, 1,7-octadiene,vinylcyclohexane, 4-vinylcyclohexene, allylbenzene, divinylbenzene,2,5-norbornadiene, and mixtures of such other preferred monomers withC₂₋₂₀ α-olefins.

In general, the polymerization may be accomplished at conditions wellknown in the prior art for Ziegler-Natta or Kaminsky-Sinn typepolymerization reactions, i.e., temperatures from 0°-250° C. andpressures from atmospheric to 10,000 atmospheres (0.1 to 1000 MPa).Suspension, solution, slurry, gas phase or other process conditions maybe employed if desired. In most polymerization reactions the molar ratioof catalyst:polymerizable compounds employed is from 10⁻¹²:1 to 10⁻¹:1,more preferably from 10⁻¹²:1 to 10⁻⁵:1.

Suitable solvents or diluents for polymerization may be noncoordinating,inert liquids. Examples include C₄₋₁₀ straight and branched-chainhydrocarbons, especially butane, isobutane, pentane, isopentane, hexane,heptane, octane, and mixtures thereof; cyclic and alicyclic hydrocarbonssuch as cyclopentane, cyclohexane, cycloheptane, methylcyclohexane,methylcycloheptane, and mixtures thereof; perfluorinated hydrocarbonssuch as perfluorinated C₄₁₀ alkanes, and aromatic and alkyl-substitutedaromatic compounds such as benzene, toluene, and xylene (all isomers).Suitable solvents also include liquid olefins or other monomers ormixtures thereof.

Thus, in some embodiments, the catalysts are used to polymerize a lowerα-olefin, particularly ethylene or propylene, most preferably ethylene,at a preferred temperature within the range from 0° C. to 200° C.,preferably 25° C. to 100° C. and at a preferred pressure within therange from atmospheric to 6,894 kPa (1000 psig) preferably 100 kPa to3,400 kPa (15 to 500 psig). The catalysts will be used either tohomopolymerize ethylene or to copolymerize ethylene with a secondmonomer that may be a lower alpha-olefin having from 3 to 8 carbon atoms(including styrene) thereby yielding a plastic or an elastomericcopolymer. In both the embodiments, the monomers will be maintained atpolymerization conditions for a nominal holding time within the rangefrom about 1 to about 60 minutes. Thus, polymerization conditions thatmay vary include pressure, temperature, time, solvent type, solvent tomonomer ratio, residence time, catalyst to activator ratio, scavengerpresence or amount, comonomer presence or amount, monomer to comonomerratio, catalyst to solvent ratio, catalyst to monomer ratio andcombinations thereof.

Libraries can be synthesized on diverse substrates made of differentmaterials or having different topological characteristics and the effectof the nature of the support on the compounds synthesized can beexamined as described above. In certain embodiments, the substrate canalso comprise a synthesis support.

B. Synthesis Supports and Substrates

In a preferred embodiment, the library comprises an array of supportedmetal-ligand compounds. In general, if supported organometalliccompounds or catalysts are synthesized, the metal-ligand compounds areattached directly to either a substrate or a synthesis support for thelibrary of organometallic compounds or catalysts. In other embodiments,the metal-ligand compounds are attached to the substrate or synthesissupport via a linker-arm.

The structure, shape and functional characteristics of the substrate arelimited only by the nature and scale of the reactions performed usingthe substrate. In certain embodiments, the substrate comprises a porousmaterial. In other embodiments, the substrate is a nonporous material.The substrate can be substantially flat or can contain wells or raisedregions. The substrate can have an integral means for liquid transfersuch as, for example, holes, needles, valves, pipets or combinationsthereof. The substrate can also comprise a means for conductingreactions under an inert or controlled atmosphere. Thus, in oneembodiment, the substrate further comprises a cover which has a meansfor purging the substrate and its contents with a particular atmosphere.In other embodiments, the substrate contains means for heating orirradiating with light, sound or ionizing radiation the materials on orwithin the substrate. In yet a further embodiment, the substratecomprises a means for agitating the material within or upon thesubstrate.

In a preferred embodiment, the substrate has a substantially flat uppersurface with a plurality of indentations or wells of sufficient depth toallow a quantity of synthesis support to be contained within theindentations or wells during reaction with one or more added reagents.

The substrate is constructed of any material which can be formed into aconfiguration which allows for the synthesis and screening of thelibrary of the invention. The only limitation upon the materials usefulfor constructing substrates is that they must be compatible with thereaction conditions to which they will be exposed. Thus, substratesuseful in practicing the methods of the invention include, but are notlimited to, organic and inorganic polymers, metal oxides (e.g., silica,alumina), mixed metal oxides, metal halides (e.g., magnesium chloride),minerals, quartz, zeolites, TEFLON, crosslinked, noncrosslinked ordentrimeric polyethylene, polypropylene, copolymers, polypropylene,polystyrene, and ceramics. Other configurations for substrates andmaterials from which substrates can be constructed will be apparent tothose of skill in the art. Soluble catalysts can be adsorbed ontoinorganic or organic substrates to form useful heterogeneous catalysts.

In an exemplary two-dimensional combinatorial library of supportedorganometallic compounds or catalysts, wherein a synthesis support isutilized, the following substrate synthesis support configurations arepossible: i) a porous support is placed in wells wherein the reactantsflow through the support from the top of the well out through a hole inthe bottom of the well (or flow may be in the reverse direction); ii) aporous support is placed in wells wherein the reactants flow only intoand out of the top of the well; iii) a non-porous support is placed inwells wherein the reactants flow around the substrate from the top ofthe well out through a hole in the bottom of the well (or flow may be inthe reverse direction); iv) a non-porous support is placed in wellswherein the reactants do not flow through from top to bottom of thewell, but only to and from the top of the well; or v) a non-porous orporous support that is not contained in wells wherein the reactants aredeposited directly onto the substrate surface in a spatially addressablemanner.

In embodiments in which a ligand or synthesis support is intended to beattached to the substrate, the substrate is functionalized to allow thisattachment. In embodiments wherein the ligand is synthesized by bringingtogether ligand fragments on the substrate, the substrate isfunctionalized to allow the attachment of a first ligand fragment. Inembodiments wherein the ligand or synthesis support is not bound to thesubstrate, the substrate can be either functionalized orunfunctionalized.

Functionalizable substrates are known in the art. For example, glassplates have been functionalized to allow the conjugation ofoligonucleotides thereto (see, e.g., Southern, Chem. Abstr. 1990,113:152979r). Another method to functionalize glass is taught byBrennan, T. M., et al. (U.S. Pat. No. 5,474,796, herein incorporated byreference), which comprises using polar silanes containing either ahydroxyl or amino group. Organic polymers are also amenable tofunctionalization. For instance, polypropylene can be surfacederivatized by, for example, chromic acid oxidation, and subsequentlyconverted to hydroxy- or amino-methylated surfaces which provide anchorsfor ligands, ligand fragments or synthesis supports. Other polymers foruse in practicing the instant invention include, for example, highlycrosslinked polystyrene-divinylbenzene which can be surface derivatizedby chloromethylation and subsequent functional group modifications.Nylon surfaces can also be derivatized as they provide an initialsurface of hexylamino groups.

Similar to the substrate, the synthesis support can be an organicpolymeric material or inorganic material including, but not limited to,alumina, silica, glass quartz, zeolites, TEFLON, etc. Depending on thematerial the synthesis support is composed of, it can be a porous,textured, or solid material, and may be flat or in the form of beads orany other geometric shape. Synthesis supports comprising, for example,functionalized polystyrene, polyacrylamide and controlled pore glass areknown in the art. Jones, J., “AMINO ACID AND PEPTIDE SYNTHESIS,” OxfordScience Publications, Oxford, 1992; Narang, S., Ed., “SYNTHESIS ANDAPPLICATIONS OF DNA AND RNA,” Academic Press, Inc., New York, 1987, andreferences therein which are herein incorporated by reference.Additionally, methods appropriate for functionalizing substrates arealso appropriate for functionalizing materials intended for use assynthesis supports. Once the substrate or synthesis support isfunctionalized, a ligand or ligand component is attached thereto.

C. Ligands

The method of the present invention is broadly applicable to all ligandswhich are capable of binding metal ions. The combinatorial variation ofthe ligand can be achieved through a solid-phase or solution-phasereaction or reactions. Alternatively, a sequence comprising acombination of solid-phase and solution-phase reactions can be used tosynthesize an array of metal-binding ligands. Ligand characteristicswhich can be varied using the methods of the present invention include,but are not limited to, the number of coordination sites on the metalwhich the ligand can occupy, the charge and electronic influence of theligand, the geometry imposed on the metal by the ligand, the geometryimposed on the ligand by the metal, etc. A plethora of metal-bindingligands are known in the art and other ligands and ligand parametersamenable to variation using the methods of the instant invention will beapparent to those of skill in the art. See, for example, Collman, J. P.,et al PRINCIPLES AND APPLICATIONS OF ORGANOTRANSITION METAL CHEMISTRY,University Science Books, California, 1987, and references therein whichare herein incorporated by reference,

In a preferred embodiment, the general approach is; 1) synthesis ofligand libraries comprising ligands (e.g., ancillary ligands) capable ofstabilizing low coordination number (e.g., three to five) metal alkylcomplexes in a variety of geometric configurations (e.g., trigonal,tetrahedral, square planar, square pyramidal, pentagonal andbipyramidal); 2) forming metal complexes of these libraries; 3)optionally reacting libraries of the metal complexes with variousactivators and/or modifiers; and 4) screening the resulting libraries ofmetal complexes for various properties and characteristics, for example,olefin polymerization activity, polymerization performancecharacteristics, etc. In an alternative embodiment, the activated metalcomplexes can be immobilized on a library of supports and/or linkers andthen assayed for various properties (e.g., olefin polymerizationactivity, polymerization performance characteristics). In a particularlypreferred embodiment, the metal ion is a transition metal ion.

In a preferred embodiment, the ancillary ligand binds to the metalcenter and stabilizes it in a low coordination number and docs notdirectly participate in the catalytic chemistry. Although lower numbersof coordination sites are typically preferred, embodiments utilizinglarger numbers of coordination sites are not precluded. When the numberof coordination sites is three or greater, the metal-ligand compound canhave more than one geometry.

In another preferred embodiment, the coordination sites of the ancillaryligand are 1, 2, 3 or 4, and the charge on the ligands are 0, −1, −2, −3or −4. Other ancillary ligands include those wherein the charge isgreater than the number of sites it occupies. Due to the nature of theirstructure, certain ligands will have more than one possible coordinationnumber and/or more than one possible charge. For example, a ligand'scharge and/or coordination number can be different when it is bound todifferent metals such as an early- or a late-transition metal ion. Byway of further example, a ligand which is deprotonated under stronglybasic conditions, e.g., n-butyllithium, and contacted with a metal ioncan have a different coordination number and/or charge than the sameligand has when reacted with a metal ion under milder conditions.

Examples of ligand, metal-ligand complexes and catalyst families whichcan be used in the methods of the present invention include, but are notlimited to, the following:

(1) One-site, monoanionic ancillary ligands such as Cp*MR₂ ⁺NCA⁻(wherein M represents the metal, R is an alkyl and NCA=non-coordinatinganion), and mono-Cp systems in combination with methylalumoxane (MAO);

(2) Two-site, dianionic ancillary ligands, which include, for example,bis-Cp systems (referred to in U.S. Pat. Nos. 4,752,597 and 5,470,927,the teachings of which are incorporated herein by reference); mono-Cpsystems where a heteroatom based ancillary ligand occupies the secondsite (referred to in U.S. Pat. No. 5,064,802, the teachings of which areincorporated herein by reference); non-Cp, bis-amide systems (referredto in U.S. Pat. Nos. 5,318,935 and 5,495,036, the teachings of which areincorporated herein by reference); and bridged bis-amido ligands andGroup IV catalysts stabilized by ligands (referred to in Organometallics1995, 14:3154-3156 and J. Am. Chem. Soc. 1996, 118:10008-10009, theteachings of which are incorporated herein by reference);

(3) Two site, monoanionic ancillary ligands including, for example,Cp(L)CoR⁺X⁻ and related systems (referred to in WO 96/13529, theteachings of which are incorporated herein by reference);

(4) Two site, neutral ancillary ligands, for example, the Ni²⁺ and Pd²⁺systems. See, for example, Johnson, et al., J. Am. Chem. Soc. 1995,117:6414-6415 and WO 96/23010, the teachings of which are incorporatedherein by reference;

(5) Three site, neutral ancillary ligands;

(6) Three site, monoanionic ancillary ligands;

(7) Three site, dianionic ancillary ligands;

(8) Three site, trianionic ancillary ligands;

(9) Four site, neutral, monoanionic and dianionic ancillary ligands; and

(10) Ancillary ligands where the charge is greater than the number ofsites it occupies (see, for example, U.S. Pat. No. 5,504,049, theteachings of which are incorporated herein by reference).

One application of the present invention is the preparation andscreening of large numbers of ligands which are components oforganometallic compounds or catalysts. Ligands which are used inpracticing the instant invention include as part of their the bindingdomain of their structural motif groups such as, for example, alkyl,carbene, carbyne, cyanide, olefin, ketone, acetylene, allyl, nitrosyl,diazo, dioxo, disulfur, diseleno, sulfur monoxide, sulfur dioxide, aryl,heterocycles, acyl, carbonyl nitrogen, oxygen, sulfur, phosphine,phosphido and hydride. Additional atoms and groups comprising ametal-binding domain are known in the art and are useful in practicingthe instant invention. See, for example, Collman, J. P., et al.PRINCIPLES AND APPLICATIONS OF ORGANOTRANSITION METAL CHEMISTRY,University Science Books, California, 1987, and references therein whichare incorporated herein by reference.

As explained above, the libraries of ancillary ligands are made usingcombinatorial chemistry formats. Within the library, a wide range ofligand characteristics can be varied. Characteristics which are variableacross the library include, for example, the ligand's bulk, electroniccharacter, hydrophobicity/hydrophilicity, geometry, chirality, thenumber of coordination sites on the metal that the ligand occupies, thecharge on both the ligand core and its substituents, and the geometrythe ligand imposes on the metal.

Bi-, tri- and tetra-dentate ligand systems which lend themselves tocombinatorial synthesis can be constructed, for example, from thefollowing ligand fragments which are listed according to their charge.

The synthesis of said ligand libraries can be carried outcombinatorially (parallel or split pool methods) using variations ofestablished synthetic organic methods. Neutral ligand fragments include,but are not limited to, amine (R₃N), phosphine (R₃P), arsine (R₃As),stilbines (R₃Sb), ethers (R₂O), thioethers (R₂S), selenoethers (R₂Se),teluroethers (R₂Te), ketones (R₂C═O), thioketones, imines (R₂C═NR),phosphinimine (R₃P═NR, RP═NR, R₂C═PR), pyridines, pyrazoles, imidazoles,furans, oxazoles, oxazolines, thiophenes, thiazoles, isoxazoles,isothrazoles, arenes, nitriles (R—C≡N), isocyanides (R—N≡C), acetylenes,olefins.

Monoanionic ligand fragments include, but are not limited to, amides(NR₂), phosphide (PR₂), silyl (SiR₃), arsido (AsR₂), SbR₂, alkoxy (OR),thiol (SR), selenol (SeR), tellurol (TeR), siloxy (OSiR₃),cyclopentadienyl (C₅R₅), boratobenzenes (C₅BR₆) pyrazoylborates,carboxylate (RCO₂ ⁻), acyl (RCO), amidates, alkyl, aryl, triflates(R₃CSO₃ ⁻), thiocarboxylate (RCS₂ ⁻), halide, nitrate, and the like.

Dianionic ligand fragments include, but are not limited to,cycloctatetrenyl (R₈C₈ ²⁻), alkylidenes (R₂C), borylides (C₄BR₅), imido(RN), phosphido (RP), carbolide, oxide, sulfide, sulphate, carbonate,and the like.

Trianionic ligand fragments include, but are not limited to, alkylidynes(R—C≡), —P³⁻ (phosphides), —Ar (arsides), phosphites.

Multidentate ligands can generally be constructed by bridging ligandfragments through one or more of the pendent R-groups. Specific examplesof bidentate neutral ligands [2,0] which may be constructed from thelist of ligand fragments set forth above, include, but are not limitedto, diimines (derived from two imine fragments), pyridylimines (derivedfrom a pyridine and imine fragment), diamines (derived from two aminefragments), imineamines (derived from an imine and an amine),iminethioether (derived from and imine and a thioether), imineethers(derived from an imine and an ether), iminephosphines (derived from animine and a phosphine), bisoxazoline (derived from two oxazolines),diethers (derived from two ethers), bisphosphineimines (derived from twophosphineimines), diphosphines (derived from two phosphines) andphosphineamine (derived from a phosphine and amine). Other bidentateneutral ligand systems can be similarly constructed from the list ofneutral ligand fragments set forth above.

Bidentate monoanionic ligands [2,1] can be constructed by bridging aneutral ligand fragment with a monoanionic ligand fragment from thelists set forth above. Examples include, but are not limited to, salenand other alkoxy imine ligands (derived from imine and alkoxy ligandfragments), amidoamines (derived from an amide and an amine) andamidoether (derived from an amido and ether). Other bidentate monoamineligands can be similarly constructed.

Bidentate dianionic ligands [2,2] can be constructed either by combiningtwo monoanionic ligand fragments or a dianionic ligand fragment and aneutral ligand fragment. Specific examples include, but are not limitedto, dicyclopentadienyl ligands (derived from two cyclopentadienyl ligandfragments), cyclopentadienyl amido ligands (derived from acyclopentadienyl and amide ligand fragments), imidothioether ligands(derived from an imido and thioether ligand fragments), imidophosphineligands (derived from imide and phosphine ligand fragments) andalkoxyamide ligands (derived from alkoxide and amide ligand fragments).Other bidentate diamine ligands can be similarly constructed.

Bidentate ligands having charges greater than −2 can be constructed bycombining monoanionic ligand fragments with di- or tri-anionic ligandfragments, or by combining two dianionic ligand fragments. Examplesinclude bisimido ligands (derived from two imide ligands), and carbyneether ligands (derived from carbyne and ether ligand fragments).

Tridentate neutral ligands [3,0] can be constructed by combining threeneutral ligand fragments from the list set forth above. Examplesinclude, but are not limited to, 2,5 diimino pyridyl ligands (derivedfrom two imine and one pyridyl ligand fragments), triimidazoylphosphines (derived from three imidazole ligand fragments bonded to acentral phosphorus atom), tris pyrazoyl alkanes (derived from threepyrazole ligands bonded to a central carbon atom). Other tridentateneutral ligands (e.g., [3,1], [3,2], [3,3]) can be similarlyconstructed.

In preferred embodiments, the coordination numbers (CN) of the ancillaryligand are independently 1, 2, 3 or 4, and the charge on the ligands areindependently 0, −1, −2, −3, or −4. The ancillary ligand or ligandfragment needn't be negatively charged, for example, positively chargedligands, such as, tropylium (C₇H₇ ⁺), are also of use in practicing thepresent invention.

The presently preferred “families” of the coordination numbers andcharges are: (i) CN=2, charge=−2; (ii) CN=2, charge=−1, (iii) CN=1,charge=−1; (iv) CN=2, charge=neutral; (v) CN=3, charge=−1; (vi) CN=1,charge=−2; (vii) CN=3, charge=−2; (viii) CN=2, charge=−3; (ix) CN=3,charge=−3(x) CN 4, charge=−2. In other preferred embodiments, theancillary ligand has a charge which is greater than the number ofcoordination sites it occupies on a metal ion.

Other preferred embodiments of ligand families that lend themselves tocombinatorial synthesis strategies and are depicted herein are: (1)Ancillary ligand on a support wherein, CN=2, charge=neutral, denoted,[2,0]; (2) Ancillary ligand on a support wherein, CN=2, charge=−1,denoted, [2,1]; (3) Ancillarly ligand with metal complex on a supportwherein, CN=2, charge=−2, denoted, [2,2]; (4) Ancillary ligand offsupport wherein, CN=2, charge=−1, denoted, [2,1]; (5) Ancillary ligandoff support wherein, CN =2, charge=−2, denoted, [2,2]; (6) Ancillaryligand off support with a functional linker, wherein, CN=2, charge=−2,denoted, [2,2]; (7) Ancillary ligand off support with a “functionless”linker, wherein, CN=2, charge=−2, denoted, [2,2]; and (8) Ancillaryligand off support wherein, CN=3, charge=−3, denoted, [3,3].

FIG. 3 set forth another possible route for catalyst precursor synthesisusing the combinatorial synthesis approach of the present invention. Ingeneral, one can imagine other libraries of ligand cores that can bemade using similar combinatiorial chemistry formats. Examples includethe ligand cores displayed in FIGS. 4A-G.

An important example of this invention is the placement of the acidicfunctionality on the R-group substituents within a library. The acidicfunctionality can have profound effects on the catalytic performance ofthe polymerization catalyst system, including improving the ability ofthe catalyst to rapidly incorporate polar functional comonomers. Latetransition metal catalysts, such as the Brookhart catalyst, toleratecertain polar functional comonomers; however, the rate of polymerizationis greatly reduced due to intramolecular coordination of the polarfunctionality to the metal center (see, FIG. 13A). Proper placement ofan acid moiety of the acillary ligand would compete with the metalcenter for coordination of the polar functional group and accelerate therate of polymerization by creating a vacant coordination site at themetal center as depicted in FIG. 13B. Suitable acidic functionalitiesinclude, but are not limited to, trivalent boron groups, trivalentaluminum groups, carboxylic acids and sulfuric acids. The inclusion ofacidic functionality on the R-groups of the ancillary ligand system is ageneral concept applicable to all ligand/metal complexes of thisinvention.

The ligands of the invention, particularly the diimine ligands, can beeither symmetric or asymmetric. The symmetric ligands contain twomoieties each derived from identical imines. In contrast, the asymmetricligands will contain two moieties each derived from non-identicalamines. A number of synthetic routes can be used to arrive at theasymmetric ligands. For example, one carbonyl group of the diketone canbe protected while the other is reacted with an amine. Followingdeprotection, the second carbonyl group is reacted with a second amine.Another useful reaction pathway consists of adding an approximatelystoichiometric amount of a first amine followed by the addition of asimilar amount of a second amine. Other routes to both symmetric andasymmetric ligands will be apparent to those of skill in the art.

The R groups pendent from the ancillary core are chosen for thecharacteristics which they impart to the organometallic compounds. Rgroups affect the reactivity and stability of catalysts andorganometallic compounds but do not bind directly and irreversibly tothe metal center. The size and electronic nature of the R groups can bevaried to alter the bulk around the metal center and the electronicproperties of the ligand-metal compound. R groups which are chiral canimpart chirality to the ligand-metal complex. Further R groups are usedto adjust the hydrophobicity/hydrophilicity of the ligand-metalcompound.

The R groups on the ligands are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, acyl, halogen, amino, cyano,nitro, hydroxy, alkoxy, alkylamino, acylamino, silyl, germyl, stanyl,siloxy, phosphino, aryloxy, aryloxyalkyl, substituted aryloxyalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, heterocycles, substituted heterocycles,heterocyclicalkyl, substituted heterocyclicalkyl S-aryl and S-alkylmercaptans.

The term “independently selected” is used herein to indicate that the Rgroups, e.g., R₁, R₂ and R₃, can be identical or different (e.g., R₁, R₂and R₃ may all be substituted alkyls or R₁ and R₂ may be a substitutedalkyl and R₃ may be an aryl, etc.). Adjacent R-groups may be coupled toform cyclic structures.

A named R group will generally have the structure which is recognized inthe art as corresponding to R groups having that name. For the purposesof illustration, representative R groups as enumerated above are definedherein. These definitions are intended to supplement and illustrate, notpreclude, the definitions known to those of skill in the art.

The term “alkyl” is used herein to refer to a branched or unbranched,saturated or unsaturated, monovalent hydrocarbon radical. When the alkylgroup has from 1-6 carbon atoms, it is referred to as a “lower alkyl.”Suitable alkyl radicals include, for example, methyl, ethyl, n-propyl,1-propyl, 2-propenyl (or allyl), n-butyl, t-butyl, i-butyl (or2-methylpropyl), etc. As used herein, the term encompasses “substitutedalkyls.”

“Substituted alkyl” refers to alkyl as just described including one ormore functional groups such as lower alkyl, aryl, acyl, halogen (i.e.,alkylhalos, e.g., CF₃), hydroxy, amino, alkoxy, alkylamino, acylamino,acyloxy, aryloxy, aryloxyalkyl, mercapto, both saturated and unsaturatedcyclic hydrocarbons, heterocycles and the like. These groups may beattached to any carbon of the alkyl moiety.

The term “aryl” is used herein to refer to an aromatic substituent whichmay be a single aromatic ring or multiple aromatic rings which are fusedtogether, linked covalently, or linked to a common group such as amethylene or ethylene moiety. The common linking group may also be acarbonyl as in benzophenone. The aromatic ring(s) may includesubstituted or unsubstituted phenyl, naphthyl, biphenyl, diphenylmethyland benzophenone among others.

“Substituted aryl” refers to aryl as just described including one ormore functional groups such as lower alkyl, acyl, halogen, alkylhalos(e.g. CF₃), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy,mercapto and both saturated and unsaturated cyclic hydrocarbons whichare fused to the aromatic ring(s), linked covalently or linked to acommon group such as a methylene or ethylene moiety. The linking groupmay also be a carbonyl such as in cyclohexyl phenyl ketone.

The term “acyl” is used to describe a ketone substituent, —C(O)R, whereR is alkyl or substituted alkyl, aryl or substituted aryl as definedherein.

The term “amino” is used herein to refer to the group —NRR′, where R andR′ may independently be hydrogen, lower alkyl, substituted lower alkyl,aryl, substituted aryl or acyl. When an amino group is bonded to a metalthrough the nitrogen atom, it is referred to as an “amido” ligand.

The term “alkoxy” is used herein to refer to the —OR group, where R isan alkyl, substituted lower alkyl, aryl, substituted aryl, wherein thesubstituted alkyl, aryl, and substituted aryl groups are as describedherein. Suitable alkoxy radicals include, for example, methoxy, ethoxy,phenoxy, substituted phenoxy, benzyloxy, phenethyloxy, t-butoxy, etc.

As used herein, the term “mercapto” defines moieties of the generalstructure R—S—R′ wherein R and R′ are the same or different and arealkyl, aryl or heterocyclic as described herein.

The term “saturated cyclic hydrocarbon” denotes groups such as thecyclopropyl, cyclobutyl, cyclopentyl, etc., and substituted analogues ofthese structures.

The term “unsaturated cyclic hydrocarbon” is used to describe amonovalent nonaromatic group with at least one double bond, such ascyclopentene, cyclohexene, etc. and substituted analogues thereof.

The term “heteroaryl” as used herein refers to aromatic rings in whichone or more carbon atoms of the aromatic ring(s) are substituted by aheteroatom such as nitrogen, oxygen or sulfur. Heteroaryl refers tostructures which may be a single aromatic ring, multiple aromaticring(s), or one or more aromatic rings coupled to one or morenonaromatic ring(s). In structures having multiple rings, the rings canbe fused together, linked covalently, or linked to a common group suchas a methylene or ethylene moiety. The common linking group may also bea carbonyl as in phenyl pyridyl ketone. As used herein, rings such asthiophene, pyridine, isoxazole, phthalimide, pyrazole, indole, furan,etc. or benzo-fused analogues of these rings are defined by the term“heteroaryl.”

“Heteroarylalkyl” defines a subset of “alkyl” wherein the heteroarylgroup is attached through an alkyl group as defined herein.

“Substituted heteroaryl” refers to heteroaryl as just described whereinthe heteroaryl nucleus is substituted with one or more functional groupssuch as lower alkyl, acyl, halogen, alkylhalos (e.g., CF₃), hydroxy,amino, alkoxy, alkylamino, acylamino, acyloxy, mercapto, etc. Thus,substituted analogues of heteroaromatic rings such as thiophene,pyridine, isoxazole, phthalimide, pyrazole, indole, furan, etc. orbenzo-fused analogues of these rings are defined by the term“substituted heteroaryl.”

“Substituted heteroarylalkyl” refers to a subset of “substituted alkyls”as described above in which an alkyl group, as defined herein, links theheteroaryl group to the nucleus.

The term “heterocyclic” is used herein to describe a monovalentsaturated or unsaturated nonaromatic group having a single ring ormultiple condensed rings from 1-12 carbon atoms and from 1-4 heteroatomsselected from nitrogen, phosphorous sulfur or oxygen within the ring.Such heterocycles are, for example, tetrahydrofuran, morpholine,piperidine, pyrrolidine, etc.

The term “substituted heterocyclic” as used herein describes a subset of“heterocyclics” wherein the heterocycle nucleus is substituted with oneor more functional groups such as alkyl, acyl, halogen, alkylhalos(e.g., CF₃), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy,mercapto, etc.

The term “heterocyclicalkyl” defines a subset of “alkyls” wherein analkyl group, as defined herein, links the heterocyclic group to thenucleus.

The term “substituted heterocyclicalkyl” defines a subset of“heterocyclic alkyl” wherein the heterocyclic nucleus is substitutedwith one or more functional groups such as lower alkyl, acyl, halogen,alkylhalos (e.g., CF₃), hydroxy, amino, alkoxy, alkylamino, acylamino,acyloxy, mercapto, etc.

In a preferred embodiment, an array of ligand moieties is synthesized ona substrate. This array is a combinatorial array of spatially separatedsurrate- or synthesis support-bound ligand moieties. Any of thepreviously discussed ligand types are amenable to this synthesisstrategy; however, in a preferred embodiment, the array of ligandmoieties comprises neutral bidentate ligands or chelating diimineligands. Following its synthesis, the array of ligand moieties can bebound to a metal ion (e.g., transition metal ion, main group metal ion,and lanthanide ions).

In another preferred embodiment of this invention, a metal-ligand arrayor library is prepared such that each member of the ligand array iscontacted with a metal ion precursor in the presence of a suitablesolvent, wherein the metal-ligand array comprises neutral bidentateligand moieties and the metal precursor is stabilized by at least onelabile neutral Lewis base. Transition metal ion precursors areparticularly preferred. In another preferred embodiment, the ligandmoieties are diimine ligands and the transition metal precursor isselected from a Group 10 transition metal. In yet another preferredembodiment, the ligands are monoanionic bidentate ligand moieties andthe transition metal precursor is stabilized by at least one labileanionic leaving group ligand.

In a preferred embodiment of this invention, ligand libraries describedherein can be reacted with main group metal precursors to producecatalyst libraries. Such catalyst libraries are used for a variety oforganic transformations requiring Lewis acidic sites, includingstereo-selective coupling reactions (where a chiral Lewis acid isrequired), olefin oligomerization and olefin polymerization. As exampleof such reactions involves the reaction of trialkylaluminum with [2,2]or [2,1] ligand libraries, wherein each member of the ligand library isin the di- or mono-protic form respectively. This reaction will produceorganometallic libraries comprising bidentate ligands bound to mono- ordi-alkylaluminum centers. Such libraries can further be modified byreaction with an ion-exchange activator, such as [PhNMe₂H]⁺[B(C₆F₅)₄]⁻,to produce ligand-stabilized cationic aluminum reagents that are capableof acting as catalysts for organic coupling reactions, olefinoligomerization, and olefin polymerization. Examples of such [2,2] and[2,1] reactions are displayed below in Scheme 1:

These compounds are useful as catalysts in, for example, thepolymerization of organic monomers. Organic monomers include, but arenot limited to, ethylene, propylene, butene, isobutylene, hexene,methylacrylate, methyl vinyl ether, dienes, etc. Reactions can becarried out in gas phase or in solution, either on or off the substrateor synthesis support. The ability to assay catalytic properties of ametal-ligand compound on the substrate or synthesis support allows oneto make libraries of catalysts bound to a variety of substrates orsynthesis supports such as polystyrenes, silica, alumina, etc.

In still another preferred embodiment of this invention, a polymer blendis produced such that at least two members of the metal-ligand librariesare contacted with at least one cocatalyst and at least one monomer. Inyet another preferred embodiment, olefins, diolefins and acetylenicallyunsaturated monomers are polymerized such that at least two members ofthe metal-ligand library are contacted with at least one cocatalyst andwith at least one monomer.

Another exemplary library comprises diimine ligands of the generalformula set forth below (I). These libraries can be synthesized bysolution- or solid-phase methodologies or a combination thereof.

Substituent groups R¹, R², R³ and R⁴ can be chosen from a wide varietyof organic fragments as discussed above. The role of the R groupsubstituent is to modify the steric, stereochemical, solubility andelectronic properties of the ligand system. The R group can be polar ornonpolar, and comprise neutral, acidic or basic functionalities.Suitable R groups include those described above and also organometalloidradicals, such as, for example, silyl or germyl radicals. The molecularweight of the R group substituent will, in general, range from 1 to10,000 daltons. Polymeric or oligomeric R groups having molecularweights greater than 10,000 can also be prepared.

The diimine ligand libraries described above can be contacted with avariety of metallic precursors to form organometallic libraries. In onemethod, the ligand library is contacted with a coordinativelyunsaturated metallic precursor or a metallic precursor complexed by aweakly bound leaving group ligand as depicted below in Scheme 2.

wherein:

L is a neutral Lewis base, n is an integer greater than or equal tozero;

z is an integer greater than or equal zero;

“a” represents the number of displaced L groups, and a+z=n;

M is a metal;

X is an anionic ligand such as halide, hydrocarbyl or hydride; and

m represents the number of X ligands, and is an integer greater than orequal to zero.

Metal catalysts comprising non-coordinating anions can be synthesized bycontacting a low valent metal precursor with the protonated form of aligand library. For example, diimine stabilized transition metalcatalysts can be prepared by a two step procedure comprising: 1)reacting the diimine library with the Bronsted acid of anon-coordinating anion to form an iminium salt library, and 2)contacting the iminium salt library with a suitable low valent metallicprecursor. An example of such a process is depicted below in Scheme 3.

In certain embodiments, the ligands of the invention are made as purestereo-, regio- or conformational isomers or, alternatively, the ligandscan be a mixture of isomers. Metals suitable for use in the presentinvention include, but are not limited to, Cr, Mo, W, Pd, Ni, Pt, Ir,Rh, Co, etc. Activators suitable for use in the methods of the presentinvention include, but are not limited to, MAO, [H(OEt₂)]⁺[BAr₄]⁻, etc.Solvents suitable for use in the methods of the present inventioninclude, but are not limited to, hexane, CH₂Cl₂, toluene, CHCl₃, etc.

The techniques described above are used to synthesize more than 3, morethan 10, more than 20, more than 50, more than 100, more than 200, morethan 500, more than 1,000, more than 10,000, more than 100,000 differentcompounds. Chemical synthesis steps can be conducted with a combinationof solid-phase and solution-phase steps on substrates or synthesissupports such as pins, beads, or in wells. The methodology for varyingligands can be performed through either the parallel dispensing ofreagents to spatially addressable sites, or by known “split-and-pool”combinatorial methodology.

The methods of the present invention also encompass embodiments whereinthe linkage between the ligand and the substrate or synthesis support isvaried in length and/or chemical composition.

D. Linkers

Combinatorial libraries can also be used to identify the optimalattachment of an organometallic catalyst to a substrate or solid support(e.g., silica, alumina, polystyrene, etc.). In another embodiment of thepresent invention, linker groups are interposed between the substrateand the ligand and/or the synthesis support and the ligand and/or thesubstrate and the synthesis support. A wide variety of cleavable andnoncleavable linker groups are known to and used by those of skill inthe various chemical arts and can be used in the present invention toassemble ligand and organometallic libraries. The length and structureof the linkers are potential variables which can affect catalystperformance and can be an element of library design. Examples of linkerssuitable fort use in the methods of the present invention are describedin greater detail in PCT US94/05597, the teachings of which areincorporated herein by reference.

E. Metals

Once formed, the ligand libraries of the present invention can becontacted with metal ions to produce organometallic compounds. Thesecompounds are typically catalysts. The metal ions are in the form ofsimple salts, mixed salts or organometallic compounds.

When the methods of the invention are used to discover an activecatalyst, all classes of metal ions can be used. Broad classes of metalions for use in practicing the instant invention include, but are notlimited to, transition metal ions, lanthanide ions, main group metals,and actinide ions.

F. Immobilized Reagents

In practicing the instant invention to produce combinatorial solutionlibraries it is useful to use one or more immobilized reagents whichaccomplish different tasks. Thus, encompassed within the presentinvention is the use of, for example, immobilized bases, acids, protonsponges, oxidants, reductants, acylation and alkylation catalysts andthe like. Many such immobilized agents are known to and used by those ofskill in the art.

G. Non-Coordinating Anions (NCA)

The presence, in a catalyst, of anions which are non- orweakly-coordinated to the metal center is known in the art to yieldenhanced catalyst reactivity compared to those catalysts in which theanion is coordinated to the metal center (See, for example, U.S. Pat.Nos. 5,198,401; 5,278,119; 5,502,017 and 5,447,895, the completedisclosures of which are incorporated by reference herein).

Anions which are bulky, highly stable and non-coordinating to thecationic metal center and which exhibit strong Lewis acidity and highreactivity are of particular utility in practicing the presentinvention. In preferred embodiments, the non-coordinating anions areboron-containing structures. In more preferred embodiments, thenon-coordinating anions are boron tetraaryl structures in which the fouraryl structures are substituted with one or more electron withdrawingsubstituents (e.g., fluorine) and at least one bulky R group to increasethe solubility and the thermal stability of the organometallic orcatalyst system. Representative R groups are as discussed above in thecontext of ligands. In preferred embodiments, the R groups are C₁ to C₂₀alkyl or C₁ to C₂₀ alkyl-substituted group 14-metalloids (e.g., silicon,germanium or tin). Other non-coordinating ions of use in practicing thepresent invention will be apparent to those of skill in the art.

H. Diimine Catalyst Library Design and Synthesis

Having broadly set forth the principles and methods for thecombinatorial synthesis of arrays of ligands and organometalliccompounds, the design and synthetic methodologies for creating solutionand solid phase libraries of diimine ligands and organometalliccomplexes will now be described.

FIG. 27 illustrates the design of a 96-well ligand and ligand-metalsolid-phase library using Merrifield resin and the chemistry describedin the Examples section. The library is composed of 48 diimine ligandsderived from a Merrifield Resin-bound diketone precursor and 48substituted anilines. The Merrifield Resin-bound diketone precursor isadded to each of the 96-wells in the microtiter plate. An excess of eachaniline is added to two of the wells within the microtiter plate, andthe reactions are carried out and worked up using the protocolsdescribed in the Examples section. Ni and Pd metal ion precursors arecombined with each resulting resin-bound diimine to produce the desiredcatalyst precursor. The catalyst precursors can be activated usingappropriate activators and screened for activity and performance usingthe techniques described in the present invention.

Solution-phase diimine ligand and catalyst libraries can also beprepared using the methods of this invention. Solution-phasecombinatorial chemistry is greatly facilitated by the use of solid-phasereagents which either catalyze reactions, deliver reagents or adsorbbyproducts and/or unreacted starting materials. The general approach asit relates to the parallel synthesis of diimine ligands and thecorresponding metallic complexes is displayed in FIG. 28 and describedin Section 1.1 of the Examples section. Variation of the ligand backbonesubstitution (i.e., R₁ and R₂) can be accomplished by utilizing a largevariety of commercially-available 1,2-diketones, examples of which areillustrated in FIG. 29. The solution-phase imine condensation can becatalyzed by, for example, a variety of solid-phase immobilizedLewis-acid catalysts/dehydrants (FIG. 30). Examples include:

[PS]—CH₂—O—TiCl₃;

[PS]—CH₂—O—AlCl₂;

[PS]—SO₂—O—TiCl₃;

[PS]—SO₂—O—AlCl₂;

[PS-PEG]—TiCl₄;

[PS-PEG]—AlCl₃;

[SiO₂]—(O)_(4-n)—TiCl_(n); and

[SiO₂]—(O)_(3-n)—AlCl_(n).

In one embodiment, these catalysts are employed in conjunction with asolid-phase proton scavenging reagent such as [PS]—CH₂-piperidine.

Selective scavenging of excess aniline in the presence of diimines canbe accomplished with a variety of solid-phase reagents. Examplesinclude:

[PS]—C(O)Cl+[PS]—CH₂-piperidine;

[PS]—SO₂Cl+[PS]—CH₂-piperidine;

[PS]—NCO; and

[PS]—NCS.

III. Screening of Combinatorial Libraries

A. Introduction

The success of combinatorial chemistry depends upon the ability to firstsynthesize collections (libraries) of molecular compounds (members)where each compound has a unique elemental composition, and then torapidly characterize each compound to identify compounds havingspecific, desired properties.

The present invention provides systems and methods for the analysis oflibraries of catalysts and organometallic compounds. In the interest ofsimplicity, the analytical methods of the present invention aregenerally exemplified by reference to their use with libraries ofcatalytic compounds. Such use is not intended to limit the scope of theanalytical methods which are also applicable to the analysis oflibraries of organometallic compounds. A more complete description ofsystems and methods for interrogating large arrays of differentcompounds can be found in a commonly assigned provisional applicationentitled “SYSTEMS AND METHODS FOR RAPID SCREENING OF LIBRARIES OFDIFFERENT MATERIALS”, Serial No. 60/050,949, filed Jun. 11, 1997,(Attorney Docket No. 16703-000900), the complete disclosure of which isincorporated herein by reference for all purposes.

The use of combinatorial chemistry for discovering and optimizing newmaterials requires the existence of spatially selective, high throughputmethods for measuring such properties as activity, i.e., turnover,selectivity in converting reactants into desired-products, and stabilityduring operation under a wide variety of substrate concentrations andreaction conditions. The “philosophy” of combinatorial screening isquite different from that of conventional quantitative analyticalchemistry. Rather than striving for precise determination of accuratenumerical values of material properties, in combinatorial screening theprimary objective is the rapid, comparison of the properties of theindividual members on each library relative to each other. This mayrequire trading off quantitative accuracy for speed. Spatially selectivecharacterization methods include those capable of: (I) Identificationand characterization of gas phase products and volatile components ofthe condensed phase products; (ii) Identification and characterizationof condensed phase products; and (iii) Measurement of physicalproperties of the elements on the library.

The methods described herein include several fundamentally differentapproaches including scanned mass spectrometry and chromatography,ultraviolet, visible, infrared and other electromagnetic imaging andspectroscopy, and acoustic imaging methods. Methods for measuringcatalytic activity and specificity involve, for example, directmeasurement of product concentrations or indirect measurement of theheat of reaction. Several implementations are described which includeboth truly parallel methods of detection as well as methods that canoperate rapidly in series. In some embodiments, the parallel methodshave the common approach of integrating position sensitive photondetectors into the measurement system, while the serial methods rely oncontrolled scanning of the library or detector/source relative to oneanother. In exemplary embodiments, the present invention has the abilityto screen combinatorial libraries containing more than 10 differentmaterials on a single substrate, more than 50 different materials,alternatively more than 100 different materials, alternatively more than10³ different materials and often more than 10⁶ different materials on asingle substrate.

According to one aspect of the present invention, a variety ofembodiments are described for the identification and characterization ofgas phase products or volatile components of the condensed phaseproducts. In some of these embodiments, scanning mass spectrometry isemployed to locally measure the relative concentrations of reactants andproducts in close proximity to a catalyst compound on the library. Thelibrary elements are preferably activated by a heat source serially orin parallel. Such a system can be enhanced using laser desorptiontechniques which vaporize liquid, bound reactants and/or products in aspatially localized format and facilitate the intake of chemicals in thescanning mass spectrometry measurement system.

In a first embodiment of this aspect of the invention, a differentiallypumped mass spectrometer is employed to sample the product stream or thevolume surrounding the library compound. In a second embodiment,diffusive or supersonic molecular beam sampling are employed in adifferentially pumped mass spectrometer system, whereinoxidation-reduction of a library can be performed in situ. A thirdembodiment uses a single stage differentially pumped mass spectrometersystem with a capillary feed that can be applied to a static QMS androtatable or translatable library. In a fourth embodiment, an individualflow-through library sampling system is described. This system employsindividual flow-though paths through each library element so thatintroduction of reactants can be performed sequentially, and enablesproducts to be more concentrated in the product outlet stream. In afifth embodiment, a differentially pumped mass spectrometer with asimplified flow system is described. This flow system provides a rapidscreening method that involves a simple flow system wherein a smallvolume is created adjacent to the library and filled with reactant gasthrough an inlet port, and outlet gas is sampled by a differential massspectrometer or a gas chromatograph-mass spectrometer combination.

In preferred embodiments, the mass spectrometers of the presentinvention are capable of detecting components at aboutone-part-per-million (1 ppm), and preferably aboutten-parts-per-trillion (10 ppt). In addition, the mass spectrometers arecapable of rapidly scanning a large array of materials on a substrate,usually scanning at least 0.1 library elements per second, preferably atleast 1 library element per second, more preferably at least 10 libraryelements per second, even more preferably at least 100 library elementsper second, and often greater than 1000 library elements per second. Thehigh throughput (0.1 to greater than 1000 library elements per second),position sensitive (resolution 0.01-10 mm) methods described hereinprovides the spectrometer with the ability to quickly and reliablycharacterize large arrays of materials to optimize the materials withinthe array.

The techniques of the present invention include spatially localized MS,in which the sampling probe of the spectrometer is positioned in a novelway over individual library sites, then scanned to other sites. Inaddition, the techniques include more course screens achieved bydistancing the mass spectrometer from the library, and then heating theentire library to measure if any library members display activity ordesired products. If desired products are detected, half of the librarycan be heated and screened for desired activity or products. This“splitting” can be repeated until active sites, if any, are identified.

In another aspect of the invention, optical spectroscopy is employed toidentify and characterize gas phase products or volatile components ofthe condensed phase products. In these embodiments, library elements aretypically activated by a heat source serially or in parallel. In a firstembodiment, an ultraviolet and visible emission-excitation spectroscopyis implemented in a scanning configuration either by scanning a laserexcitation source over the catalytic surface and monitoring the emissionwith an energy specific, single photon detector, or by simultaneousexcitation with a single wavelength, while emission imaging with aposition sensitive detector. In a second embodiment, a scanningmulti-wave mixing fluorescence imaging system uses a degeneratefour-wave mixing optical technique that depends on the interaction ofthree photons to produce the fourth photon, i.e., the signal, andrequires only one wavelength, wherein the signal is a coherent beam easyto detect.

In another aspect of the invention, gas chromatography andhigh-throughput detection is employed to identify and characterize gasphase products or volatile components of the condensed phase products.Chromatography, whereby gas or liquid-phase products may be separatedand detected by their differential rates of movement through specializedadsorption/diffusion columns, is used for the measurement ofcombinatorial libraries either using conventional auto-sampling frommultiple sites or in our novel scanning configuration. Multiple columns(one each over each site, or one each over a line of sites than scanned)may be used or a single column scanned over the entire library. The“column” may be nothing more than a tube through which polymer productsmove at a rate related to their viscosity and, hence, indirectly relatedto their molecular weight.

In yet another aspect of the invention, optical methods are describedfor the identification and characterization of condensed phase products.Similar to previous embodiments, the library elements can be activatedby a heat source serially or in parallel. A first embodiment of thisaspect of the invention involves infrared absorption by evaluatingspecific molecular vibrations, wherein a monochromated IR source ispassed through the library (serially or sequentially), and the intensityof the transmitted beam measured as a function of time during theprogression of a reaction. A second embodiment employs infraredemission. For condensed phase products, which are in thermal contactwith, for example, a catalyst, infrared emission imaging of the library(in parallel or serially) provides relative differences in temperaturechange between library elements. In a third embodiment, photonscattering analysis is employed, whereby relative and time varyingdifferences in the molecular weight distribution and average molecularweight of a library for liquid products and reactants, are monitored bychanges in the relative intensity of scattered light measured as afunction of angle relative to the incident beam. In a fourth embodiment,polarized light imaging techniques are used. In these techniques, theformation of optically active crystalline domains in solids gives riseto optical rotation and/or preferential transmission of polarized light.These techniques may be carried out with a polarized light source and apolarized light detector, or, by transilluminating an entire librarywith polarized light and then imaging the transmitted light onto a CCDthrough a polarizer. Characterization of the relative changes inorientational order are monitored in real time to observe, for example,a rate of polymerization.

In another aspect of the invention, mechanical properties of the libraryelements are used to identify and characterize condensed phase products.Preferably, ultrasonic monitoring of reactions producing liquid or solidproducts are characterized by changes in the mechanical properties ofthe products by ultrasonic probing. Using the fact that the velocity ofacoustic waves is equal to the square root of the ratio of a materialsbulk modulus to its density, monitoring the ratio in every element of acombinatorial library allows the direct comparison of relative rates ofreaction and gives information as to the molecular weight distribution,etc.

In yet another aspect of the invention, identification andcharacterization of the physical properties is achieved wherein using atwo-dimensional infrared imaging system for parallel monitoring oflibrary heat of reaction, such that the entire library is monitoredsimultaneously using the heat of reaction to alter the temperature ofcompound (e.g. a solid catalyst) and surrounding support with atwo-dimensional infrared imaging camera, wherein the individual libraryelement's temperature (and its difference relative to the surroundingelements) reflects the activity of the specific library site and theheat of reaction.

In addition to the gas phase analysis methods described above for thevolatile (or vaporizable) product components of condensed phaseproducts, methods have been developed for characterizing the condensedphase products themselves on the library surface. Such products whichmight be encountered, for example, in the gas phase polymerization ofethylene to condensed phase polyethylene or hydrolysis of liquiddimethyldichlorosilane to elastomeric polydimethylsiloxane. Thesemethods of high throughput screening are sensitive to the optical andmechanical properties of the substrates. The optical methods describedprovide a means of parallel screening for both specificity and activityusing infrared absorption and emission as well as the opticalpolarization and scattering of the condensed phase products. Screeningfor mechanical properties cannot be used for the detection of specificproducts, however, for reactions (such as polymerization) where the rateof change of bulk properties reflect the rate of catalysis (degree ofpolymerization), measurements of bulk properties provides a method ofrapid screening for desirable reaction kinetics.

Generally, the two-dimensional combinatorial catalysis library elementswill be synthesized either on a porous substrate such as, for example,alumina or silica, or on an impermeable substrate in one of the twoconfigurations depicted schematically in cross section in FIG. 14. Thesubstrates (shown in white in FIG. 14) are non-reactive materials of anytwo-dimensional shape that is convenient for scanning, such as circulardisks, rectangles, squares, etc. The substrate's function is to positionand isolate the elements of the catalyst library in the reactant stream.The substrate can contain indentations or “wells” to contain the libraryelements which consist of the catalyst compound possibly present on asupport material, i.e., on a synthesis support.

As shown in FIG. 14A, in the first configuration, the sample chamber isfilled with reactant gas A at a pressure P and individual catalystelements (the catalyst compound alone or the compound deposited on asupport) are selectively activated by focused IR heating or by resistiveheating elements incorporated into the substrate. All library elementsare in contact with the reactant gas at a pressure P; however, only whenheated will the catalyst posses significant activity to produceappreciable products. The library can, for example, be cooled to avoidany side reactions.

In the second configuration set forth in FIG. 14B, a permeable substrateis utilized and reactant gas at a pressure P on top of the library isdriven through the supported catalyst library element and then bothunreacted reactants and products pass through the porous substrate intoa region of lower pressure where the products are detected. The flow canbe directed though one element path at a time by sealed conduits or,alternatively, it can be directed through all elements simultaneously.Individual elements can be selectively heated for serial measurement ofthe products or the entire library heated for parallel characterization(e.g., optical emission imaging). This method has the advantage that thepressure drop across the substrate allows the gas detection system tosample a lower pressure stream.

B. Identification and Characterization of Gas Phase Products or VolatileComponents of the Condensed Phase Products

Reactions producing gas phase products are monitored, for example, bydevices capable of spatially selective mass spectroscopy, spatiallyselective optical spectroscopy (resonant-enhanced multiphoton ionizationand UV-visible absorption-emission) and gas chromatography.

1. Gas Phase Characterization by Mass Spectroscopy

Mass spectroscopy (MS) is a well established method of analyticalchemistry for the identification of chemical species. The systemsdescribed herein are applicable both to spatially localized MS, whereinthe device is positioned in a novel way over individual catalyticlibrary sites, and to more course screens, wherein the MS is distancedfrom the library and the entire library is heated to measure if anylibrary members display catalytic activity or desired products. In thelatter embodiment, if desired products are detected, half of the librarycan be heated and screened for desired products. This “splitting” can berepeated until active sites, if any, are identified.

In one particular embodiment of the mass detection strategy, a massspectrometer capable of detecting a one-part-per-million (1 ppm)component in one atmosphere background pressure has been developed. Thissystem involves a pinhole opening on the order of about 0.01 mm to about0.5 mm and, more preferably, 0.05 mm to about 0.2 mm to sample the downstream gas mixture after it has passed through the mini-catalyst bed,followed by three-stage differential pumping, electron-impact ionization(or photo-ionization) and quadruple mass detector. The catalyst libraryis contained on a disk that is scanned in the X-Y plane so that everysite can be accessed. Depending on the rate of the reactions, real-timekinetics can be followed by this approach.

(i) Differentially Pumped Mass Spectrometer that Samples Product Streamor Volume Surrounding the Library Compound:

Measurement of the gas phase reaction products is achieved in severalways, each with advantages depending on the library. The most directmeasurement uses a highly sensitive species dependent probe, such as adifferentially pumped mass spectrometer, to sample the product stream orthe volume surrounding the library compound. The first approach involvescareful positioning of the mass spectrometer sampling tube over eachelement (or in the product stream) and analyzing the products of eachlibrary element serially as depicted in FIG. 15. Each library element isindividually addressed/activated by a scanned IR heating source toinsure product production only in individual elements and to limit sidereactions and catalyst aging (alternatively, individual resistiveheaters can be incorporated into the substrate). This implementationassumes that the activity of the catalyst is negligible until it isheated.

In a presently preferred embodiment, the library is physically scannedin front of a fixed heating source- detector nozzle or through fixedinlet and outlet tubes that are sealed against the library around eachindividual element serially (see, e.g., FIG. 16). Alternatively, thelibrary can be fixed and the detector assembly and heater scanned.

(ii) Supersonic Molecular Beam Sampling System:

The Supersonic Molecular Beam Sampling System (SMBSS) depicted in FIG.17 uses a differentially pumped mass spectrometer system, and can beapplied to a variety of systems. The substrate can be SiO₂ (e.g.,oxidized Si wafer) clamped in a susceptor. Oxidation-reduction of alibrary is performed in situ, and heating of the library can beperformed simultaneously or sequentially, using IR or patternedconductors on the back of the substrate for resistive heating. Thesubstrate can, for example, contain insertable plugs of supportedcatalyst.

The library can have the dimensions: 1 mm×1 mm pixels with c/c spacingof 2 mm (this is the scale of the drawing depicted). On a 3¼ inch by 3¼inch substrate, this gives a 40×40 array, i.e., 1600 catalysts perlibrary substrate. Alternatively, a library of 2 mm×2 mm catalysts witha c/c spacing of 4 mm gives a library of 20×20 or 400 differentcatalysts. Alternatively, a library of 0.1 mm×0. 1 mm elements with ac/c spacing of 0.2 mm gives a library of 400×400 or 160,000 differentcatalysts.

In a particular example of this three stage differentially pumpedsystem, the substrate consists of an approximately 4½ inches×4½ inchesof a chemically inert thermal insulator material into which the silicondioxide or alumina pellets containing catalyst library elements arepressed. Each sample element is an approximately 4 mm disc. This givesrise to 625 catalysts per library. The sampled gas will be between about1 and 5 atm off the library and enter the first stage through a 100micron aperture. This gives rise to an entrance flux of approximately2.6×10¹⁹ molecules per second. The first stage pressure will be 1.1×10⁻³torr using a 1000 l/s turbo molecular pump (TMP). The first stageskimmer has a larger aperture of 200 microns giving rise to a fluxthrough the skimmer 1.2×10¹⁴ molecules per second. The 200 micronskimmer separates the first stage region (at 1.1×10⁻³ torr) from thesecond stage which is maintained at a pressure of 1.9×10⁻⁸ torr by a 200l/s TMP. The final stage skimmer has a 400 micron aperture expected toextract 9.2×10⁹ molecules/s in a molecular beam into the final stagemaintained at approximately×10⁻¹¹ torr (with a diffuse scatteredpressure of approximately 8×10⁻¹³ torr) using a 200 l/s TMP.

The effective beam pressure (flux) at the detector is estimated to beapproximately 10⁻³ torr (4.1×10¹⁶ molecules/cm²-s) which will provideample signal for reliable detection. A schematic is shown in FIG. 17 andillustrates the infra-red heating of the detector element sample below aquadruple mass spectrometer nozzle.

(iii) Single Stage Differentially Pumped Mass Spectrometer:

The Single Stage Differentially Pumped Mass Spectrometer system with acapillary feed, depicted in FIG. 18, uses a single-stage differentiallypumped mass spectrometer system. This system can be applied to a staticQMS and rotatable or translatable library. The heat source is, forexample, IR from below or above the substrate. The entire library can heheated to oxidize or reduce the catalysts. Also, the entire library canbe heated during the reaction to assess whether any catalyst is active.

Although numerous variations of this implementation exist, the basicconfiguration is depicted in FIG. 18, wherein sampling occurs from acircular disc library. Sampling a reactor pressure of 10³ torr either asmall capillary or aperture area of approximately 1.96×10⁻⁷ cm² connectsthe quadruple mass spectrometer chamber to the high pressure region. Thepressure within the mass spectrometer chamber is approximately 7.2×10⁻⁶torr (upper limit) which can be achieved using a 270 liter per secondturbo molecular pump. Various lengths of capillary or orifice tapers canbe used. In the schematic set forth in FIG. 18, if the inlet flow rateis 0.1 liters per second and the pumping speed approximately 1 liter persecond, then the steady state reactor pressure is 100 torr and theresonance time is 5 seconds assuming the reactor volume is 5 liters. Inthe schematic, a circular sample stage is depicted using a 3 inch waferand 6.35 mm diameter sample discs. In this implementation 16 differentcatalysts can be used.

(iv) Individual Flow-Through Library Sampling:

The Individual Flow-Through Libraries system is similar to the EmbeddedCatalyst Impregnated in Micro-porous Silica Capped by Macro-porousSilica system described below in (vi), except that this embodimentemploys individual flow-though paths through each library element sothat introduction of reactants can be performed sequentially. Thissystem provides a distinct advantage in that it enables products to bemore concentrated in the product outlet stream.

In an individual flow through library implementation, typically fewercatalysts library elements will be utilized (for example, 8×12=96catalysts). This gives the advantage of extremely high concentrations ofproducts in the outlet stream. The flow into the vacuum side will bedictated by pressure drop through the porous support for 1 cc/s at 1000torr this gives rise to 3.5×10¹⁹ molecules per second. The vacuumpressure will be 0.2 torr using a 10 micron diameter orifice into thequadruple mass spectrometer at 100 l/s turbo molecular pumping speedgives rise to a pressure in the mass spectrometer of 1.7×10⁻⁸ torr. See,FIG. 16.

(v) Differentially Pumped Mass Spectrometer with a Simplified FlowSystem:

A rapid screening method that involves a relatively simple flow systemand requires only a scanned IR source is depicted schematically in FIG.19. A “small” volume is created adjacent to the library and filled withreactant gas A through an inlet port. Selective IR heating of a thinsubstrate activates a catalyst element of interest which producesproducts into the volume. The outlet gas is then sampled by adifferential mass spectrometer (or if a large number of high molecularweight products exist, a gas chromatograph can be implemented prior tothe mass spectrometer to separate the products). Maintaining a smallvolume above the library will improve the sensitivity of the massspectrometric detection. A high surface area support should be used ineach catalyst element. To reduce parasitic reactions at other sites, thelibrary can be maintained at low temperature and only the active elementheated.

A similar arrangement can be configured for a flow-through geometrywhereby the inlet is placed on the opposite side of the library as theoutlet and the substrate is porous to allow gas passage through eachmember. Heating of the substrate can also be performed by (i)selectively heating regions of, for example, 10 elements, (ii) screeningproduct formation by detecting the average of the signal from the 10elements, then (iii) focusing in on individual elements in the selectedregions that produce significant signals. This strategy is referred toas a deconvolution strategy.

(vi) Embedded Catalyst Impregnated in Micro-porous Silica Capped byMacro-porous Silica:

In another embodiment, the present invention employs a Embedded CatalystImpregnated in Micro-porous Silica Capped by Macro-porous Silica systemwhich uses a differentially pumped mass spectrometer system.Differential heating of individual catalyst volumes will increasediffusivity of reactants and products through the membrane locally atthe catalyst being examined. This provides a distinct advantage to thissystem that will enable products to be more concentrated in the reactorvolume (above the membrane) being sampled by the mass spectrometer.

In this system, the substrate is depicted in an up-side-downconfiguration, wherein gas can flow through all of the library elementssimultaneously, driven by a pressure gradient wherein the pressure atthe bottom is greater than the pressure at the top. Detection isperformed from the top (back of the substrate) in the lower pressureenvironment. The heat source is, for example, IR or resistance, and isapplied sequentially to each element.

In this implementation, the high pressure zone is in contact with thecatalyst so the catalyst sees the high pressure (working pressure) ofthe chamber system. This will replicate the in practice conditions. Ifthe pressure behind the plug is greater than 1000 torr, P_(o) isadjusted to be approximately 10⁻³ torr. (This can be done with aroughing pump and membrane porosity). If the orifice is 1 micron tosample into the mass spectrometer, this give rise to a flux of 3.2×10¹⁷molecules/cm²-s. The leak rate is 2.5×10¹⁵ molecules/s and assuming a100 l/s turbo molecular pump, P₁ is 7.8×10⁻⁷ torr.

2. Gas Phase Characterization by Optical Spectroscopy:

(i) Ultraviolet and Visible Emission-Excitation Spectroscopy:

For library characterization, traditional ultraviolet and visibleemission-excitation spectroscopy has been implemented in a scanningconfiguration by 1) scanning a laser excitation source (uv-vis),member-by-member, over the catalytic surface and subsequently monitoringthe emission with an energy specific, single photon detector asillustrated in FIG. 20. In this embodiment, individual library elementsare heated with a focussed infrared source or the entire library may beheated uniformly. Products produced must contain a desired product witha distinct excitation-emission signature with high efficiency. Theexcitation source tuned to the desired product is focussed directly onor above the element (or on a cooled condensation membrane positioneddirectly above the element) and the emission monitored in an energyselective emission photodetector.

A second embodiment, illustrated in FIG. 21, is a parallel extension ofthe above method which operates by simultaneous excitation of the entireheated library area with the single product excitation wavelength, whileemission imaging with a position sensitive detector, such as a CCDthrough a bandpass filter specific for the desired product emission asillustrated in FIG. 21.

(ii) Scanning Multi-wave Mixing Fluorescence Imaging:

The spectroscopic techniques of degenerate four-wave mixing (DFWM) andlaser-induced fluorescence (LIF) have been applied to the detection ofminor species for combustion diagnostics at high sensitivities (Mann, B.A., et al., “Detection and imaging of nitrogen dioxide with thedegenerate four-wave-mixing and laser-induced-fluorescence techniques,”Applied Optics, Jan. 20, 1996, 35(3):475-81.). Degenerate four-wavemixing is a nonlinear optical technique that depends on the interactionof three photons to produce the fourth photon, i.e., the signal. Itrequires only one wavelength and, thus, it is relatively simple to setup. The signal is a coherent and directional beam (unlike fluorescencewhich is emitted in all directions) and is therefore easy to detect athigh sensitivity (approximately 10,000 molecules under favorableconditions). The technique has a spatial resolution determined, in part,by the localization of the lasers (in practice approximately 10microns). The selectivity of this technique relies on the absorptionproperties of the species being detected and can be thought of as beinganalogous to absorption spectroscopy, except that it is more sensitive,more selective and has a higher spatial resolution.

For library scanning, the optical detection system has a configurationsimilar to the Supersonic Molecular Beam Sampling System, describedabove, in-so-far-as the library format, heating and motion may be usedfor faster screening. The optical detection uses a dual wavelength laserdetection system whereby one laser is used for excitation and anotherfor absorption spectroscopy. The sensitivity of these methodologies areapproximately 10⁻¹⁸ molar (one atmosphere of an ideal gas gives rise2.7×10¹⁹ molecules per cm³).

3. Gas Phase Characterization by Gas Chromatography:

(i) Gas Chromatography:

Gas chromatography is another general purpose means of characterizinggas phase products. The method for simple samples is well known to thosefamiliar with the art. High-throughput measurement of libraries can beused for the rapid screening of catalysts. In one application,multi-port injection valve can sample a sequence of catalyst sitesrapidly. A multi-column system can be used if higher throughput isrequired. Mass spectrometry and chromatography are generally used ascomplementary techniques and like the scanning mass spectrometer(above), a scanning chromatograph configuration whereby the library isscanned under the GC intake may be used for HTS.

C. Characterization of Condensed Phase Products

In addition to the gas phase analysis methods described above for thevolatile (or vaporizable) product components of condensed phaseproducts, methods have been developed for characterizing the condensedphase products themselves on the library surface. Such products whichmight be encountered, for example, in the gas phase polymerization ofethylene to condensed phase polyethylene or hydrolysis of liquiddimethyldichlorosilane to elastomeric polydimethylsiloxane. Thesemethods of high throughput screening are sensitive to the optical andmechanical properties of the substrates. The optical methods describedprovide a means of parallel screening for both specificity and activityusing infrared absorption and emission as well as the opticalpolarization and scattering of the condensed phase products. Screeningfor mechanical properties cannot be used for the detection of specificproducts, however, for reactions (such as polymerization) where the rateof change of bulk properties reflect the rate of catalysis (degree ofpolymerization), measurements of bulk properties provide a means ofrapid screening for desirable reaction kinetics.

1. Condensed Phase Product Characterization by Optical Methods:

(i) Infrared Absorption:

Specific molecular vibrations can be evaluated by infrared absorptionand the method applied to single samples well known. For example,because C═C stretch modes have specific absorptions at 1650 and 2200cm⁻¹, monitoring the relative change in absorption at those frequenciesover a library, will provide a measure of the relative changes in thenumber of C═C bonds in the system and, therefore, reflect, for example,the polymerization of ethylene (see, FIG. 22).

In a typical embodiment, an infrared source monochromated to the desiredwavelength using selective filtering is passed through the library andthe intensity of the transmitted beam is measured as a function of timeduring the progression of the reaction. The source can be directedthrough individual library elements one-by-one in serial fashion asdepicted in FIG. 22, or a large area source beam can be passed throughthe entire library and a position sensitive IR detector, such as HgCdTeor InSb, can be used to monitor an infrared transmission image as afunction of time giving a parallel measurement. Reflectance modemeasurements may also similarly be performed.

Using a large area infrared source achieved either with a beam expander(IR laser) or a bandpass filtered lamp source the entire library may beilluminated simultaneously and using a focal plane array or similararray detector the IR reflectance or transmissions monitored in parallelfashion. Furthermore, as described below in more detail (part C) for gasphase catalysis, the heat of reaction as measured by temperature changescan be used as a screening method of catalytic rate. Though insensitiveto specific products, when activity is of interest, this method gives aparallel high throughput screen. Condensed phase products will be inthermal contact with the catalyst and infrared emission imaging of thelibrary elements as depicted in FIG. 26 provides a unique means ofscreening large libraries in parallel.

For rapid throughput screening, the relative differences in temperaturechange between library elements is satisfactory, and only those elementswith relatively large temperature changes need to be more carefullyexamined with high activity catalysts are the target. If largedifferences in emissivity are observed for individual library elements,then the imaging can be done of the uniform substrate in thermal contactwith the catalyst and support.

(ii) Photon Scattering Analysis:

Light scattering from condensed phase polymers and suspensions is a wellestablished method of materials analysis. A unique implementation ofphoton scattering has been created whereby relative and time varyingdifferences in the molecular weight distribution and average molecularweight of a library of catalysts for liquid products and reactants aremonitored by changes in the relative intensity of scattered lightmeasured as a function of angle relative to the incident beam (see, FIG.23). A photodiode array positioned around a library element is used tocollect the scattered light intensity as a function of angle relative tothe incident laser. The library is scanned relative to thelaser-detector subassembly for the purpose of mapping the property as afunction of position on the library. Several sweeps of the library canbe used to characterize the temporal changes in the scattered lightdistribution to follow, for example, rate of polymerization.

Although precise quantitative determination of the Rayleigh ratio andaverage molecular weight requires careful design of the scattering cellgeometry (usually cylindrical), for relative measurements, moreconvenient practical configurations can be used. Similarly, precise workusing only small angle scattering allows simplification of thescattering-function and use of the straight-forward Debye equation todetermine accurately average molecular weights, however, since forlibrary screening relative changes are desired to choose compounds formore precise secondary characterization larger angle scattering may beused.

(iii) Polarized Light Imaging:

The formation of optically active crystalline domains in solids can giverise to optical rotation and/or preferential transmission of polarizedlight. Using the schematic diagram of the IR system described above andillustrated in FIG. 17, except replacing the IR source and detector witha polarized light source and a polarized light detector, or bytransilluminating an entire library with polarized light and thenimaging the transmitted light onto a CCD through a polarizer,characterization of the relative changes in orientational order can bemonitored in real time to observe the rate of polymerization in manyimportant polymer systems.

2. Condensed Phase Product Characterization by Mechanical Properties

(i) Ultrasonic Monitoring:

Catalysis of reactions producing liquid or solid products are monitoredand characterized by changes in mechanical properties of the productsmeasured by ultrasonic probing. The velocity of acoustic waves is equalto the square root of the ratio of a material's bulk modulus to itsdensity. Although both density and modulus may change during theformation of products, monitoring the ratio in every element of acombinatorial library allows the direct comparison of relative rates ofreaction and gives information regarding the molecular weightdistribution. Measurement of the surface acoustic wave velocity is alsopossible by acoustic monitoring (Rayleigh Waves). The Rayleigh wavevelocity gives a measure of the Poisson ratio of the material whichtogether with the bulk modulus completely determines the mechanicalproperties of a solid material. Therefore, acoustic characterization notonly measures changes in properties relevant for polymerization andother catalytic processes, it also measures the important mechanicalproperties of the resulting material and is a well known method ofcharacterizing materials.

Two different embodiments of acoustic monitoring to combinatoriallibrary characterization are provided. The first embodiment, illustratedin FIG. 24, uses an ultrasonic imaging transducer-lens system coupledthrough a coupling medium (e.g., water, mercury, etc.) to the base of acombinatorial library containing catalyst. There can be an array of manytransducer-lens systems or a single transducer-lens that is scannedacross the base of the library.

The second embodiment consists of a piezoelectric transducer (PZT) array(either separate or incorporated into the library substrate), with eachelement of the PZT array directly adjacent to a library element. The PZTelement serves as both the transmitter of acoustic energy and thereceiver. Monitoring of the acoustic velocities requires onlymultiplexing the array for serial readout. Two, slightly different,integrated designs would have the substrate itself be a PZT materialwith electrodes attached directly under each library element, or withthe PZT pads attached or deposited directly under the individual libraryelements. The latter implementation is illustrated in FIG. 25.

D. Measurement of Physical Properties of the Catalyst Library

1. Characterization by Heat of Reaction:

(i) Two-Dimensional Infrared Imaging for Parallel Monitoring of CatalystLibrary Heat of Reaction:

An alternative method presented for monitoring the rate of reaction ofall the elements in the library simultaneously relies on the heat ofreaction to alter the temperature of the solid catalyst and surroundingsupport and to monitor the temperature with a two-dimensional infraredimaging camera. In the condensed phase detection system described above,the products, catalyst and support will all change temperature; however,in the gas phase, the temperature variation is limited to the catalystand support. The individual library element's temperature (and itsdifference relative to the surrounding elements), will reflect theactivity of the specific library site and the heat of reaction. Thecatalyst support should have a minimal thermal mass and it is assumedeach library element contains nearly identical catalyst surface area.One configuration of this method is depicted in FIG. 26.

The measurement begins, in one example, with the sample chamber, libraryand structure equilibrated uniformly at the temperature of the activitymeasurement. An inert gas may fill the chamber at the experimentalpressure initially or it may be evacuated or it may be in anotherinitial state. At t=0, the desired reactant gas is leaked into thechamber and the substrate temperature is measured continuously atintervals. The rise (or fall) in temperature of the thermal masssupporting the catalyst will be a direct measure of the exothermic(endothermic) catalytic activity of the site.

The sensitivity of most commercial infrared detection arrays (e.g.,HgCdTe or InSb) is better than +/−0.05° C. over the range of −50 to+800° C. and the spatial resolution is determined by the optics to bebetter than 1 mm. As an estimate of the temperature change expected, ifthere is a microjoule deposited in a 1 mm×1 mm×0.0001 mm region ofmaterial, a temperature change of approximately 0.5 K is expected. Thereaction of ethylene and hydrogen to ethane produces 120 KJ/mole and,therefore, 1 microjoule requires only the reaction of 5×10¹² molecules.Many times that number will react in a second on a 1 mm×1 mm×0.0001 mmporous support for most important industrial catalysts or on anon-porous 1 mm×1 mm×0.000001 mm film. In a less preferred embodiment,individual elements can be monitored in series using non-positionsensitive temperature detection technology or single element scanneddetectors.

The present invention is directed to the synthesis of supported andunsupported ligand molecules and their subsequent conversion toorganometallic and catalyst compounds. In the examples which follow, thesynthesis of two representative calsses of ligands, diimines andpyridylimines, using the methods of the invention are detailed.Representative examples using both solution- and solid-phasemethodologies are provided. The use of these two broad ligand classes tofurther describe the invention is intended to be exemplary and is notintended to define or limit the scope of the invention or of theligands, organometallic compounds or catalysts which can be assembledusing the methods of the instant invention.

IV. EXAMPLES

The following examples illustrate a variety of embodiments of thepresent invention. Example 1 illustrates the solution-phase synthesis ofbis-imine ligands. Example 2 illustrates the concept of solid phasecombinatorial synthesis of diimine ligands. Example 3 illustrates theapplication of the methods of the present invention to the solid phasesynthesis of diimine ligands, wherein the diimine is synthesized on thesupport. Example 4 illustrates the utility of the catalysts of thepresent invention in polymerizing olefins. Both the supported andunsupported catalysts of the invention were assayed for their ability topolymerize ethylene to poly(ethylene). The polymerization of higherolefins such as hexene was also examined. Example 5 details thepreparation of a pyridyl imine ligand and its nickel complex. Thecatalyst was used to polymerize both hexene and ethylene. Example 6illustrates reaction schemes which can be used to prepare a variety of[2,0], [2,1], and [2,2] ligand libraries. Such [2,0], [2,1], and [2,2]ligand libraries can be prepared using solution or solid phasemethodologies from a salen-based scaffold.

Example 1

Example 1 details the solution-phase synthesis of bis-imine ligandcomponents of a combinatorial library of ligands. General strategieswere developed for aryl bis-imines with both electron-donating andelectron-withdrawing groups on the aryl moiety.

1.1 Synthesis of [(2,4,6-Me₃Ph)DABMe₂]NiBr₂ through Solution-PhaseMethodology

a. Synthesis of Resin-Bound Lewis-Acid Catalyst PS—CH₂—O—TiCl₃

To 10 g hydroxymethylpolystyrene (1.12 mmol OH/g resin) swollen in 100mL of anhy. CH₂Cl₂ was added 4.24 g (2.24 mmol) TiCl₄, and thissuspension was heated to reflux under N₂ with gentle stirring for 1 h.The resin was filtered under N₂, washed with 5×50 mL anhy. CH₂Cl₂ andthen dried under high vacuum for 24 h. Chloride analysis (9.98%)provided a loading of 0.94 mmol TiCl₃/g resin.

b. Synthesis of Aniline Scavenging Reagent PS—SO₂Cl

To 10 g of PS—SO₂—OH (Amberlyst 15, washed with MeOH and dried in vacuo;ca. 5 mmol OH/g resin) in 50 mL of anhy. CH₂CL₂ was added 3 g (25 mmol)of SOCL2. This mixture was heated at reflux under N₂ for 18 h. The resinwas filtered under N₂, washed with 5×50 mL of anhy. CH₂Cl₂, then driedunder high vacuum for 24 h. Chloride analysis (16.05%) provided aloading of 4.53 mmol SO₂Cl/g resin.

c. Ligand Synthesis

To a suspension of 250 mg (0.24 mmol) of PS—CH₂—OTiCl₃ and 93 mg (0.25mmol) PS—CH₂-piperidine in 5 mL of anhy. CH₂Cl₂ was added 676 mg (0.5mmol) of 2,4,6-trimethylaniline followed by 8.6 mg (0.1 mmol)2,3-butanedione. This mixture was shaken at RT for 24 h. then filteredand washed with 2×1 mL anhy. CH₂Cl₂. GC analysis showed2,4,6-trimethylaniline and the product (2,4,6-Me₃Ph)DABMe₂ in anapproximately 3:1 ratio.

d. Excess Aniline Scavenging

To the 3:1 mixture of 2,4,6-trimethylaniline and (2,4,6-Me₃Ph)DABMe₂ wasadded 111 mg of PS—SO₂Cl and 185 mg of PS—CH₂-piperidine and thismixture shaken at RT for 12 h. The resin was filtered and washed with2×0.5 mL CH₂Cl₂. The filtrate was evaporated to provide 285 mg (89%) of(2,4,6-Me₃Ph)DABMe₂ as yellow crystals.

e. Synthesis of [(2,4,6-Me₃Ph)DABMe₂]NiBr₂ Complex

A suspension of 285 mg (0.89 mmol) of (2,4,6-Me₃Ph)DABMe₂ and 274 mg(0.89 mmol) (DME)NiBr₂ in 5 mL CH₂Cl₂ was shaken in a sonication bath atRT for 24 h. The resultant solid was collected by filtration and washedwith 3×1 mL CH₂Cl₂ to provide 456 mg (95%) [(2,4,6-Me₃Ph)DABMe₂]NiBr₂ asa red powder.

1.2 Preparation of (2,4,6-Me)₂DAB(Me)EtPh Nickel (II) Dibromide

(2,4,6-Me)₂DAB(Me)EtPh (0.50 g, 1.17 mmol) and (DME)NiBr₂ (0.36 g, 1.17mmol) were dissolved in 8 ml dry CH₂Cl₂ under nitrogen and stirred atroom temperature for 8 hr. The resulting reddish-brown solution wasconcentrated and the remaining residue was recrystallized fromCH₂Cl₂/hexane to afford 0.40 g of (2,4,6-Me)₂DAB(Me)EtPh nickel (II)dibromide as reddish-brown crystals in 53% yield. Anal. Cald forC₃₀H₃₆N₂NiBr₂: C, 55.88; H, 5.62; N, 4.34. Found: C, 55.08; H, 5.55; N,4.21.

1.3 Solution-phase Synthesis (Spectroscopic Model Compounds)

Compounds with all of the structural features of the immobilizedcompounds are prepared in tandem with the immobilized compounds. Themodel compounds allowed the proper spectroscopic parameters to bedetermined for the immobilized analogues. Additionally, these compoundshave a catalytic activity which is similar to that exhibited by theanalogous immobilized metal-ligand compounds.

1.3(a) Alkylation of (2,4,6-Me)₂DAB(Me)Et with Benzyl Bromide

To a cooled solution (0° C.) of (2,4,6-Me)₂DAB(Me)Et (2.00 g, 5.99 mmol)in 15 ml dry THF under nitrogen was added LDA (4.40 ml, 6.59 mmol, 1.5 Min THF). After stirring at 0° C. for 2 hr, benzyl bromide (0.86 ml, 7.19mmol) was added and the resulting solution was stirred 3 hr at 0° C. and10 hr at room temperature. The reaction mixture was concentrated on arotovap and the remaining oily residue was taken up in 50 ml Et₂O andwashed with H₂O (2×50 ml). The Et₂O layer was dried over MgSO₄, filteredand concentrated. The crude material was passed through a plug of silicagel with CH₂Cl₂ and concentrated once more to afford 2.54 g of thedesired product in 95% yield as a yellow oil. ¹H NMR 300 MHz, (CDCl₃) δ7.23-7.28 (m, 3H), 7.19 (d, 2H, J=6.9 Hz), 6.98 (s, 2H), 6.94 (s, 2H),2.87 (br s, 4H), 2.64 (q, 2H, J=7.6 Hz), 2.37 (s, 3H), 2.35 (s, 3H),2.14 (s, 6H), 2.06 (s, 6H), 1.12 (t, 3H, J=7.6 Hz); ¹³C NMR 75 MHz,(CDCl₃) δ 171.97, 169.97, 145.85, 145.56, 141.15, 132.28, 132.20,128.66, 128.28, 128.15, 125.97, 124.37, 32.76, 31.28, 22.24, 20.67,18.22, 18.06, 11.24; IR (C═N) @ 1635 cm⁻¹.

1.3(b) Hydrolysis of Benzyl (2,4,6-Me)₂DAB(Me)Et (Methyl)

A stirring solution of benzyl (2,4,6-Me)₂DAB(Me)Et (0.20 g, 0.47 mmol)and oxalic acid (0.20 g, 2.35 mmol) in 10 ml THF/H₂O (5:1 v/v) washeated to 70° C. for 8 hr. After cooling to room temperature anddiluting with 30 ml Et₂O, the organic layer was washed with H₂O (2×10ml), dried over MgSO₄, filtered and concentrated. GC/MS analysisrevealed 1-phenyl-3,4-hexanedione and 2,4,6-trimethylaniline as the onlydetectable species in the crude reaction mixture. Pure1-phenyl-3,4-hexanedione (89 mg) was obtained by passing the crudemixture through a plug of silica gel in >95% yield as a colorless oil.¹H NMR 300 MHz, (CDCl₃) δ 7.20-7.31 (m, 5H), 3.14 (t, 2H, J=7.6 Hz),3.01 (t, 2H, J=7.4 Hz), 2.75 (q, 2H, J=6.7 Hz), 1.07 (t, 3H, J=6.6 Hz);¹³C NMR 75 MHz, (CDCl₃) δ 199.44, 198.25, 140.19, 128.20, 128.06,125.94, 37.34, 29.10, 28.67, 6.53; IR (C═O) @ 1712 cm⁻¹.

1.3(c) Alkylation of (2,4,6-Me)₂DAB(Me)Et with1-(Bromoethyl)-2-Methoxyethane

To a cooled solution (0° C.) of (2,4,6-Me)₂DAB(Me)Et (0.50 g, 1.48 mmol)in 15 ml dry THF under nitrogen was added LDA (1.09 ml, 1.65 mmol, 1.5 Min THF). After stirring at 0° C. for 4 hr, 1-(bromoethyl-2-methoxyethane(0.24 ml g, 0.1.79 mmol) was added with Bu₄NI (0.27 g, 0.75 mmol) andthe reaction mixture was warmed to 50° C. and stirred for 10 hr. Aftercooling to room temperature, the reaction mixture was diluted with 30 mlEt₂O and washed with H₂O (3×15 ml), dried over MgSO₄, filtered andconcentrated on a rotovap. The crude product was chromatographed with20% Et₂O/hexane (R_(f)=0.45) to afford 0.93 g of the desired product asa yellow oil in 45% yield. ¹H NMR 300 MHz, (CDCl₃) δ 6.81 (s, 2H), 3.33(s, 4H), 3.25-3.32 (m, 2H), 3.23 (s, 3H), 2.41-2.47 (m, 4H), 2.20 (s,6H), 1.94 (s, 12H), 1.54-1.69 (m, 2H), 0.94 (t, 3H, J=7.5 Hz). 13C NMR75 MHz (CDCl₃) δ 171.97, 170.35, 145.65, 145.52, 132.15, 128.56, 128.53,124.36, 71.72, 70.95, 69.48, 58.89, 27.33, 25.51, 22.19, 20.61, 18.06,11.11.

1.3(d) Preparation of (2,4,6-Me)₂DAB(1-Methoxyethoxyethyl)Et Nickel (II)Dibromide

(2,4,6-Me)₂DAB(1-methoxyethylpropyloxy) ethane (0.29 g, 0.67 mmol) and(DME) NiBr₂ (0.21 g, 0.67 mmol) were taken up in 6 ml dry CH₂Cl₂ undernitrogen and stirred at room temperature for 24 hours. The reactionmixture was filtered through celite and concentrated to afford crude(2,4,6-Me)₂DAB(1-methoxyethoxypropyl)ethyl nickel (II) dibromide whichwas purified through recrystallization from CH₂Cl₂/hexane to afford 0.35g of pure product as a reddish-brown solid in 80% yield. Anal. Cald forC₂₈H₄₀N₂O₂NiBr₂: C, 51.33; H, 6.15; N, 4.27. Found: C, 52.01; H, 6.26;N, 3.91.

1.3(e) Preparation of (2,4,6-Me)₂DAB(Me)EtPh Palladium (II) (Me)Cl

(2,4,6-Me)₂DAB(Me)EtPh (0.23 g, 0.65 mmol) and (COD)PdMeCl (0.17 g, 0.65mmol) were dissolved in 8 ml dry CH₂Cl₂ under nitrogen and stirred atroom temperature for 8 hr. The resulting orange-red solution wasconcentrated and the remaining residue was recrystallized fromCH₂Cl₂/hexane to afford 0.30 g of (2,4,6-Me)₂DAB(Me)EtPh palladium (II)(Me)Cl as a orange solid in 80% yield. Anal. Cald for C₃₁H₃₉N₂PdCl: C64.02; H 6.76; N 4.81. Found: C, 63.47; H, 6.70; N, 4.62.

1.4 Solution-phase Combinatorial Synthesis

Catalytic bis-imine formation generally works well for anilinederivatives containing electron donating groups (X=EDG). However,anilines containing electron withdrawing groups (X=EWG) are much lessnucleophilic and bis-imine formation is not observed under standardconditions (Entry 1, Table 1). Therefore, conditions were sought toinitiate bis-imine formation with a representative electron deficientaniline derivative (X=3,5-CF₃). The general scheme is displayed inScheme 10. These results are summarized in Table 1.

TABLE 1 A B Catalyst C Entry Equiv. Equiv. (Equiv.) Conditions Yield(GC/MS) 1 1 20 HCO₂H (10) CH₂Cl₂/MeOH  0% RT, 12 hr. 2 1 20 H₂SO₄ (10)CH₂Cl₂/MeOH 20% RT, 12 hr. 3 1 20 (CO₂H)₂ (10) CH₂Cl₂/MeOH 65% RT, 12hr. 4 1 10 (CO₂H)₂ (10) (CH₈O)CH  0% 70° C., 12 hr. 5 1 20 (CO₂H)₂ (10)Si(OEt)₄ 60% RT, 12 hr. 6 1 13 TiCl₄ (2) CH₂Cl₂ 80% RT, 12 hr. 7 1 15TiCl₄ (5) CH₂Cl₂ 95% RT, 12 hr.

Example 2

Example 2 illustrates the concept of solid phase combinatorial synthesisof diimine ligands. Through the approach outlined below, alkylation of adiimine ligand with 1% cross-linked (bromomethyl)polystyrene is carriedout. The supported diimine is hydrolyzed to give the corresponding resinbound diketone which serves as starting material for synthesizing abroad range of chemically diverse bis-imine ligands. The analogoussolution-phase reactions are performed in parallel and are fullycharacterized spectroscopically and serve to provide spectroscopichandles (¹H and ¹³C NMR, FTIR, Raman IR) to help facilitate thecharacterization of the desired resin bound compounds.

2.1 Solid Phase Combinatorial Strategy

This approach involves the parallel synthesis of organometalliclibraries immobilized on a polymer support. Advantages to this approachinclude exposing a large excess of the reagents to immobilizedsubstrates and effectively driving reactions to completion. Excessreagents and/or side products are then removed from the desiredimmobilized substrate by filtration followed by extensive washings.

2.2 Preparation of (Bromomethyl)Polystyrene

(Hydroxymethyl)polystyrene (2.50 g, 2.84 mmol, 0.80 mmol/g) andtriphenylphosphinedibromide (2.40 g, 5.68 mmol) were combined undernitrogen and 20 ml of dry THF was added. After stirring at roomtemperature for 24 hr, the resin was filtered and washed extensivelywith THF (3×20 ml), DMF (3×20 ml), CH₂Cl₂ (3×20 ml), and dried underhigh vacuum to afford 2.75 g of (bromomethyl)polystyrene as a beigeresin. A loading capacity of 0.58 mmol/g was calculated based on bromideanalysis (4.65% Br).

2.3 Alkylation of (2,4,6-Me)₂DAB(Me)Et with (Bromomethyl)Polystyrene

To a cooled solution (0° C.) of (2,4,6-Me)₂DAB(Me)Et (0.50 g, 1.49 mmol)in 15 ml dry THF under nitrogen was added LDA (1.09 ml, 1.49 mmol, 1.5 Min THF). After stirring at 0° C. for 2 hr, (bromomethyl)polystyrene(1.06 g, 0.75 mmol) was added and the resulting suspension was stirredfor 3 hr at 0° C. and 10 hr at room temperature. The resin was filtered,washed with THF (2×10 ml), H₂O (2×20 ml), CH₂Cl₂ (2×20 ml), and driedunder high vacuum to afford 0.60 g of the desired bright yellow resin.The loading capacity of this resin was calculated to be 0.38 mmol/gbased on nitrogen analysis (1.07% N). A strong absorbance at 1635 cm⁻¹(C═N) is observed by single bead FTIR.

2.4 Hydrolysis of (2,4,6-Me)₂DAB(Me)Et (Methyl)Polystyrene

A stirring suspension of (2,4,6-Me)₂DAB(Me)Et (methyl)polystyrene (1.0g, 0.38 mmol) and oxalic acid (340 mg, 3.80 mrnmol) in 17 ml THF/H₂O(5:1 v/v) was heated to 70° C. for 12 hr. After cooling to roomtemperature and diluting with 30 ml Et₂O, the resin was filtered and thefiltrate was washed with H₂O (2×10 ml), dried over MgSO₄, filtered andconcentrated to give 24 mg of 2,4,6-trimethylaniline in 98% yield withwas >99% pure by GC/MS analysis and ¹H NMR. The beads were dried underhigh vacuum to give 850 mg of (2,3-butanedionemethyl)polystyrene. Astrong absorbance at 1712 cm⁻¹ (C═O) is observed by single bead FTIR.

2.5 Alkylation of (2,4,6-Me)₂DAB(Me)Et with (Bromo)PEG Polystyrene

To a cooled solution (0° C.) of (2,4,6-Me)₂DAB(Me)Et (0.70 g, 2.09 mmol)in 15 ml dry THF under nitrogen was added LDA (1.63 ml, 2.44 mmol, 1.5 Min THF). After stirring at 0° C. for 4 hr, (bromo) PEG polystyrene (2.33g, 0.70 mmol, 0.30 mmol/g) and Bu₄NI (0.77 g, 2.09 mmol) were added andthe reaction mixture was warmed to 50° C. and stirred an additional 8 hrafter which the resin was filtered and washed extensively with THF (3×20ml), H₂O (3×20 mi), and MeOH (3×20 ml). After drying under high vacuum,2.37 g of 2,4,6-Me)₂DAB(Me)Et (bromo)PEG polystyrene was obtained as ayellow resin. A loading capacity of 0.25 mmol/g was calculated based onnitrogen analysis (0.71% N). Magic angle spin (MAS) ¹H NMR 400 MHz,(CDCl₃) δ 6.87 (br s, 2H), 3.51 (br s, 2H), 2.76 (br s, 2H), 2.51 (d,2H, J=7.6 Hz), 2.28 (s, 6H), 2.01 (s, 12H), 1.74 (br s, 2H). 1.03 (t,3H, J=6.8 Hz).

2.6 Hydrolysis of (2,4,6-Me)₂DAB(Me)Et PEG Polystyrene

(2,4,6-Me)₂DAB(Me)Et PEG polystyrene (0.50 g, 0. 12 mmol, 0.25 mmol/g)and oxalic acid (0.10 g, 1.12 mmol) was taken up in 20 ml THF/H₂O (5:1v/v) and heated to 70° C. with gentle stirring for 8 hr. After coolingto room temperature and diluting with 25 ml Et₂O, the resin was filteredand the filtrate was washed with H₂O (2×10 ml), dried over MGSO₄,filtered and concentrated to give 16 mg of 2,4,6-trimethylaniline inquantitative yield which was >99% pure by GC/MS analysis and ¹H NMR. Thebeads were dried under high vacuum to afford 450 mg of beige2,3-butanedinone PEG resin. Magic angle spin (MAS) ¹H NMR 400 MHz,(CDCO₃) δ 2.80 (m, 2H), 1.90 (m, 2H), 1.08 (t, 3H, J=6.8 Hz).

2.7 Preparation of (2,4,6-Me)₂DAB(Me)Et Nickel (II) Dibromide PEGPolystyrene

(2,4,6-Me)₂DAB(Me)Et PEG polystyrene (0.40 g, 0.10 mmol, 0.25 mmol/g)and (DME)NiBr₂ (0.15 g, 0.50 nunol) were taken up in 10 ml dry CH₂Cl₂under nitrogen and stirred at room temperature for 12 hr. The resin wasthen washed extensively with CH₂Cl₂ and anhydrous acetone to give 0.42 gof (2,4,6-Me)₂DAB(Me)Et nickel (II) dibromide PEG polystyrene as a darkreddish-brown resin. The loading capacity of this resin was calculatedto be 0.54 mmol/g based on nickel analysis (3.40% Ni) and 0.57 mmollgbased on bromine analysis (8.67% Br), indicating that some residualnickel (II) dibromide was coordinated to the PEG polystyrene backbone.

2.8 Preparation of (2.4.6-Me)₂DAB(Me)Et Palladium (II) (Me)Cl PEGPolystyrene

(2,4,6-Me)₂DAB(Me)Et PEG polystyrene (0.50 g, 0.12 mmol, 0.25 mmol/g)and (COD)PdMeCl (0.16 g, 0.63 mmol) were taken up in 7 ml dry CH₂Cl₂under nitrogen and stirred at room temperature for 12 hr. The resin wasthen washed extensively with CH₂Cl₂ to give 0.51 g of(2,4,6-Me)₂DAB(Me)Et Pd (II) (Me)Cl PEG polystyrene as a reddish-orangeresin. Magic angle spin (MAS) ¹H NMR 400 MHz, (CDCl₃) δ 6.97 (br s, 2H),6.92 (br s, 2H), 2.75 (br s, 2H), 2.45 (br s, 2H)), 2.32 (s, 3H), 2.30(s, 3H), 2.24 (s, 6H), 2.21 (br s, 6H), 1.62 (br s, 2H), 1.03 (br s,3H), 0.36 (s, 3H).

2.9 Preparation of (2,4,6-Me)₂DAB(Me)Et Palladium (II) (ME)ClPolystyrene

(2,4,6-Me)₂DAB(Me)Et polystyrene (0.30 g, 0.11 mmol, 0.38 mmol/g) and(COD) PdMeCl (0.15 g, 0.57 mmol) were combined under nitrogen and takenup in 8 ml dry CH₂Cl₂. After stirring for 10 hr, the resin was washedextensively with CH₂Cl₂ and dried under high vacuum to afford 0.32 g of(2,4,6-Me)DAB(Me)Et palladium (II) (ME)Cl polystyrene as areddish-orange resin. The loading capacity of this resin was calculatedto be 0.32 mmol/g based on palladium analysis (4.15% Pd) and 0.39 mmol/gbased on chlorine analysis (3.39% Cl).

Example 2 demonstrates the synthesis of representative diimine ligandsutilizing the solid phase combinatorial methods of the presentinvention. The diimines of Example 2 were synthesized off of the supportand subsequently attached to the support prior to undergoing additionalmodification. Following hydrolysis of the support-attached diimines, adiketone was produced which was utilized for preparation of additionaldiimine ligands.

Example 3

Example 3 illustrates the application of the methods of the presentinvention to the solid phase synthesis of diimine ligands, wherein thediimine is synthesized on the support.

3.1 Solid-phase Bis-imine Formation

To a suspension of 2,3 butanedione (methyl)polystyrene (0.10 g, 0.08mmol) in 5 ml of dry CH₂Cl₂ was added 3,5-bis(trifluoromethyl)aniline(0.25 ml, 1.60 mmol) and TiCl₄ (0.80 ml, 0.80 mmol, 1.0 M in CH₂Cl₂).The mixture was stirred at room temperature for 24 hr upon which theresin was filtered and washed extensively with CH₂Cl₂ (3×10 ml), MeOH(3×10 ml), H₂O (3×10 ml), and dried under high vacuum to give 0.11 g ofthe desired resin. The loading capacity of this resin was calculated tobe 0.15 mmol/g based on nitrogen analysis (0.43% N).

Example 3 demonstrated that diimines can be formed directly on a resinwhich has been functionalized with a diketone.

Example 4

Example 4 illustrates the utility of the catalysts of the presentinvention in polymerizing olefins. Both the supported and unsupportedcatalysts of the invention were assayed for their ability to polymerizeethylene to poly(ethylene). The polymerization of higher olefins such ashexene was also examined.

4.1 Polymerization of Ethylene

The above resin-bound nickel(II) dibromide complex (0.16 g, 0.03 mmol)was suspended in 10 ml dry toluene upon which MAO was added (2.00 ml,300.0 mmol, 10% wt in toluene). The resin immediately turned dark blue.After stirring for 1 hr, ethylene gas was bubbled through the suspensionfor 1 min and then the reaction vessel was sealed to a pressure of 5psi. An internal thermocouple measured a 29° C. exotherm over a 20 minperiod. After stirring for an additional 1.5 hr, the temperature slowlydropped back to room temperature and the viscous solution was filteredand the beads were washed with toluene (3×10 ml). The filtrate wasconcentrated and then quenched with MeOH upon which white rubber-like(poly)ethylene formed immediately. This material was filtered and driedto give 1.60 g of (poly)ethylene. The beads were dried under high vacuumand afforded 1.60 g of material corresponding to a 10-fold mass increaseof the polystyrene beads.

An identical procedure was performed with the exception that the MAOactivated catalyst was washed with toluene (3×10 ml). After the excessMAO was filtered off, the resin-bound catalyst was taken up in 10 mltoluene prior to the introduction of ethylene. An identical outcome wasobtained to that described earlier. When this washed resin was taken upin 10 ml dry hexane instead of toluene, less (poly)ethylene was obtainedon the bead as well in the filtrate, both weighing 0.26 g.

The above example demonstrated that the supported catalysts of thepresent invention can catalyze the polymerization of olefins.

4.2 Ethylene Polymerization with [2-Ph)PMI(2,6-(Pr)₂Ph)]NiBr₂/MAO

To a suspension of 6 mg (0.01 mmol) of [2-Ph)PMI(2,6-(Pr)₂Ph)]NiBr₂ in 5mL of anhydrous, degassed toluene was added 3.3 mL (5 mmol) of 10% MAOin toluene and the resultant green solution was stirred at RT for 1 h.This solution was then flushed with ethylene and stirred under 10 psi ofethylene for 2 h. To the reaction mixture was added 4 M HCl (50 mL) andEt₂O (100 mL), the layers were separated, and the organic layer wasdried over MgSO₄. Removal of the volatiles by rotary evaporationprovided 1.3 g of polymeric material.

4.3 Polymerization of Ethylene with(2,4,6-Me)DAB(1-Methoxyethoxypropyl)Et Nickel (II) Dibromide

(2,4,6-Me)₂DAB(1-methoxyethoxypropyl)ethyl nickel (II) dibromide (0.02g, 0.03 mmol) was suspended in 15 ml dry toluene upon which MAO wasadded (2.00 ml, 300.0 mmol, 10% wt in toluene). The solution turned darkblue over a 1 hour period. After stirring for 1 hr, ethylene gas wasbubbled through the suspension for 1 min and then the reaction vesselwas sealed to a pressure of 5 psi. An internal thermocouple measured a23° C. exotherm over a 45 min period. After stirring for an additional1.5 hr, the temperature slowly dropped back to room temperature and thesolution was quenched with MeOH followed by 5 N HCl. The precipitatedpolyethylene was collected by filtration and afforded 1.38 g ofpolyethylene after drying under high vacuum.

4.4 Polymerization of Ethylene with (2,4,6-Me)₂DAB(Me)EtPh Nickel (II)Dibromide

(2,4,6-Me)₂DAB(Me)EtPh nickel (II) dibromide (0.02 g, 0.03 mmol) wassuspended in 15 ml dry toluene upon which MAO was added (2.00 ml, 9.33mmol, 10% wt in toluene). The solution turned dark blue over a 1 hourperiod. After stirring for I hr, ethylene gas was bubbled through thesuspension for 1 min and then the reaction vessel was sealed to apressure of 5 psi. An internal thermocouple measured a 19° C. exothermover a 45 min period. After stirring for an additional 1.5 hr, thetemperature slowly dropped back to room temperature and the solution wasquenched with MeOH followed by 5 N HCl. The precipitated polyethylenewas collected by filtration and afforded 2.10 g of polyethylene afterdrying under high vacuum.

The above examples demonstrated the utility of the supported andunsupported catalysts of the present invention in olefin polymerizationreactions.

4.5 Polymerization of Ethylene with (2,4,6-Me)₂DAB(Me)Et Nickel (II)Dibromide PEG Polystyrene

The above resin-bound nickel(II) dibromide resin (0.20 g, 0.02 mmol,0.10 mmol/g) was suspended in 20 ml dry toluene upon which MAO was added(2.00 ml, 300.0 mmol, 10% wt in toluene). The resin immediately turneddark blue. After stirring for 1 hr, ethylene gas was bubbled through thesuspension for 1 min and then the reaction vessel was sealed to apressure of 5 psi. An internal thermocouple measured a 3° C. exothermover a 45 min period. After stirring for an additional 1.5 hr, thetemperature slowly dropped back to room temperature and the solution wasfiltered and the beads were washed with toluene (3×10 ml). The beadswere dried under high vacuum and afforded 0.67 g of materialcorresponding to a 3-fold mass increase of the polystyrene beads. Thefiltrate afforded no polyethylene.

4.6 Polymerization of Ethylene with (2,4,6-Me)₂DAB(Me)Et Palladium (II)(Me)Cl PEG Polystyrene

The above resin-bound palladium (II) (Me)CI resin (0.20 g, 0.02 mmol,0.10 mmol/g) was suspended in 20 ml dry CH₂Cl₂ upon which NaB(Ar′)₄F wasadded (18 mg, 0.02 mmol). The resin turned brownish-red over a 1 hrperiod upon which ethylene gas was bubbled through the suspension for 1min. The reaction vessel was sealed to a pressure of 5 psi. No exothermwas observed throughout the course of the reaction. After stirring foran additional 1.5 hr, the solution was filtered and the beads werewashed with toluene (3×10 ml). The beads were dried under high vacuumand afforded 0.25 g of material corresponding to a 20% mass increase ofthe polystyrene beads. The filtrate afforded no polyethylene.

4.7 Polymerization of Ethylene with (2,4,6-Me)2DAB(Me)Et Palladium (II)(Me)Cl Polystyrene

The above resin-bound palladium (II) (Me)Cl resin (0.10 g, 0.03 mmol,0.32 mmol/g) was suspended in 25 ml dry CH₂Cl₂ upon which NaB(Ar′)₄F wasadded (30 mg, 0.03 mmol). The resin turned brownish-red over a 1 hrperiod upon which ethylene gas was bubbled through the suspension for 1min. The reaction vessel was sealed to a pressure of 5 psi. A 23° C. wasobserved throughout the course of the reaction. After stirring for anadditional 1.5 hr, the solution was filtered and the beads were washedwith toluene (3×10 ml). The beads were dried under high vacuum andafforded 0.25 g of material corresponding to a 100% mass increase of thepolystyrene beads. Workup of the filtrate afforded 2.28 g ofpolyethylene as a colorless gum. Gel permeation chromatography (toluene,23° C., polystyrene reference): M_(n)=18,518; M_(w)=31,811;M_(w)/M_(n)=1.72.

4.8 Polymerization of Ethylene with (2,4,6-Me)₂DAB(Me)Et Palladium (II)(Me)Cl

(2,4,6-Me)₂DAB(Me)Et Palladium (II) (Me)Cl (0.02 g, 0.03 mmol) wasdissolved in 25 ml dry CH₂Cl₂ upon which NaB(Ar′)₄F was added (30 mg,0.03 mmol). The solution turned brownish-red over a 1 hr period uponwhich ethylene gas was bubbled through the suspension for 1 min. Thereaction vessel was sealed to a pressure of 5 psi. A 28° C. exotherm wasobserved throughout the course of the reaction. After stirring for anadditional 2.5 hr, the solution was filtered through celite. Workup ofthe filtrate afforded 3.50 g of polyethylene as a colorless gum. Gelpermeation chromatography (toluene, 23° C., polystyrene reference):M_(n)=21,016; M_(w)=31,471; M_(w)/M_(n)=1.50.

4.9Hexene polymerization with [2-Ph)PMI(2,6-(Pr)₂Ph)]NiBr₂/MAO

To a suspension of 6 mg (0.01 mmol) of [2-Ph)PMI(2,6-(Pr)₂Ph)]NiBr₂ in 1mL of anhydrous, degassed toluene was added 3.3 mL (5 mmol) of 10% MAOin toluene and the resultant green solution was stirred at RT for 1 h.To this solution was then added 8.4 g (100 mmol) of hexene and thesolution was stirred under N₂ for 24 h. To the reaction mixture wasadded 4 M HCl (50 mL) and Et₂O (100 mL), the layers were separated, andthe organic layer was dried over MgSO₄. Removal of the volatiles byrotary evaporation provided 3.9 g (46%) of polymeric material.

Example 5

Example 5 details the preparation of a pyridyl imine ligand and itsnickel complex. The catalyst was used to polymerize both hexene andethylene. The synthetic route to the pyridyl imine nickel complex isdisplayed in Scheme 27.

5.1 Preparation of 2-acetyl-6-bromopyridine

To a solution of 3.00 g (12.7 mmol) of 2,6-dibromopyridine in 20 mLanhydrous. Et₂O at −78° C. was added dropwise over 30 min. 8.0 ML (12.8mmol) of 1.6 M n-BuLi in cyclohexane. After stirring for 3 h at −78° C.,8.2 mL (88 mmol) of N,N-dimethylacetamide was added dropwise and thesolution was stirred at −78° C. for 1 h. On warming to RT, Et₂O (100 mL)and saturated aqueous NH₄Cl (50 mL) were added and the layers wereseparated. The organic layer was dried over Na₂SO₄ and the volatileswere removed by rotary evaporation. The resulting yellow solid wasrecrystallized from hexanes to provide 1.8 g (71%) of2-acetyl-6-bromopyridine as colorless crystals. ¹H NMR (CDCl₃): σ2.81(s, 3H); 7.67-7.77 (m, 2H); 8.22 (dd, J=6.8, 1.6 Hz, 1H). Mass Spec.:m/e 200.

5.2 Preparation of 2-acetyl-6-phenylpyridine

To a Schlenk tube charged with a solution of 200 mg (1.0 mmol) of2-acetyl-6-bromopyridine and 23 mg (0.02 mmol) of (Ph₃P)₄Pd in 10 mL ofdegassed toluene was added a solution. of 150 mg (1.2 mmol)phenylboronic acid and 270 mg (2.5 mmol) Na₂CO₃ in 8 mL of degassed4:1H₂O/MeOH. The biphasic mixture was heated to 80° C. with rapidstirring for 1 h. On cooling to RT, Et₂O (50 mL) was added and thelayers were separated. The organic layer was dried over Na₂SO₄ and thevolatiles were removed by rotary evaporation. The resulting oil waschromatographed on silica with 10-50% CH₂Cl₂/hexanes eluent to provide176 mg (89%) of 2-acetyl-6-phenylpyridine as a white powder. ¹H NMR(CDCl₃); δ 2.84 (s, 3H); 7.43-7.62 (m, 3H); 7.91-8.08 (m, 3 H); 8.18 (d,J=6.6 Hz, 2H). Mass Spec.: m/e 197.

5.3 Preparation of 2-acetyl-6-phenylpyridine 2,6-di(Isopropyl)phenylimine [(2-Ph)PMI(2,6-(Pr)₂Ph)]

A solution of 197 mg (mmol) of 2-acetyl-6-phenylpyridine and 266 mg (1.5mmol) of 2,6-diisopropylaniline in 5 mL anhydrous MeOH and 0.1 mL of 0.1M H₂SO₄ in MeOH was heated to 50° C. for 12 h. The volatiles wereremoved by rotary evaporation and the crude material chromatographed onsilica with 5% EtOAc/hexanes eluent to provide 287 mg (80%) of(2-Ph)PMI(2,6-(Pr)₂Ph) as a yellow solid. ¹H NMR (CDCl₃): δ1.17 (ddd,J=4.6, 1.7, 0.7 Hz, 12H); 2.23 (d, J=2.5 Hz, 3H); 2.73 (dq, J=6.8, 2.5Hz); 7.10-7.25 (m, 3H); 7.60-7.75 (m, 2H); 7.90-8.06 (m, 2H); 8.33-8.40(m, 1 H). Mass Spec.: m/e 356.

5.4 Preparation of [(2-Ph)PMI(2,6-(Pr)₂Ph)]NiBr₂

A suspension of 71 mg (0.2 mmol) (2-Ph)PMI(2,6-(Pr)₂Ph) and 62 mg (0.2mmol) of (dimethoxyethane)nickel(II)bromide in anhydrous CH₂Cl₂ wasstirred at RT under N₂ for 48 h. The volatiles were removed by rotaryevaporation and the solid was washed several times with hexanes toprovide 101 mg (88%) of 1 [(2-Ph)PMI(2,6-(Pr)₂Ph)]NiBr₂ as an orangepowder.

The above example demonstrated that pyridyl inines can be prepared bythe methods of the present invention and that these imines are of use inpolymerizing olefins. Solid phase analogues of the above catalysts areprepared using the starting materials shown in Scheme 13 (inset), above.

Example 6

This example illustrates reaction schemes which can be used to prepare avariety of [2,0], [2,1], and [2,2] ligand libraries. Such [2,0], [2,1],and [2,2] ligand libraries can be prepared using solution or solid phasemethodologies from a salen-based scaffold using the synthetic methodoutlined in Scheme 14, wherein R¹ and R² are defined as in the sectionabove describing diimine libraries.

Scheme 28 describes chemistry relevant to both solution and solid phasemethodologies. When this chemistry is performed via solid phasechemistries the scaffold is bound to a solid particle represented by theball in the above figure.

The [2,0] ligand libraries can be converted into organometalliclibraries using the displacement or oxidative addition methods describedabove for the diimine systems. The [2,1] ligand libraries can beconverted into organometallic libraries using oxidative addition ormetathesis reactions. Oxidative addition of the heteroatom—proton boundto a low valent metal precursor to form a hydride or hydrocarbylligand-metal complex is an effective method of creating reactiveorganometallic libraries. Metathesis reactions are also useful forproducing organometallic libraries from [2,1] ligand libraries. TheBronsted acidic libraries described in the above figure can be useddirectly in metathesis reactions by contacting said libraries with metalreagents (including main group alkyls such as trimethylaluminum)containing leaving group ligands capable of abstracting the acidicproton on the [2,1] ligand. Alternatively, the [2,1] ligand librariescan be deprotonated to form metal salt libraries, which can be furtherreacted with metal complexes to undergo a metathesis reaction. Othermetathesis reactions, such as those resulting in the loss of tin orsilyl byproduct can also be envisioned.

Diamide based organometallic libraries can be prepared from diaminoligand libraries using oxidative addition or metathesis reactionssimilar to those described above. The diamino ligand libraries can beprepared using the synthetic procedure described in FIGS. 2B, 7, and 11.

Tetradentate [4,0] ligand libraries can be constructed by combining two[2,0] ligand fragments as illustrated in Scheme 15. One example of sucha combination, is illustrated in the figure below. [4,0] ligand-metallibraries can be prepared by contacting the [4,0] ligand with a suitabletransition metal precursor in a manner similar to that described for thepreparation of [2,0] bis-imine-metal libraries.

It is to be understood that the above description is intended to beillustrative and not restrictive. Many embodiments will be apparent tothose of skill in the art upon reading the above description. The scopeof the invention should, therefore, be determined not with reference tothe above description, but should instead be determined with referenceto the appended claims, along with the full scope of equivalents towhich such claims are entitled. The disclosures of all articles andreferences, including patent applications and publications, areincorporated herein by reference for all purpose.

What is claimed is:
 1. A process for parallel polymerization usingmembers of a library of potential metal-ligand polymerization catalysts,the process comprising providing a library of potential metal-ligandpolymerization catalysts wherein the concentrations or compositions ofthe potential catalysts in the library differ, and inserting thepotential catalysts into a parallel reactor and subjecting said libraryto polymerization conditions, wherein said polymerization conditionsinclude contacting said plurality of potential catalysts with at leastone monomer that is an olefin, diolefin or acetylenically unsaturatedmonomer, said parallel reactor comprising a plurality sealed reactionvessels and each of said plurality of potential catalysts being placedin a corresponding one of said plurality of vessels.
 2. The process ofclaim 1, wherein said library comprises more than 10 potential catalyststhat are each chemically different from the others.
 3. The process ofclaim 2, wherein said chemical difference is a difference is the atomsof an ancillary ligand present is said catalyst.
 4. The process of claim2, wherein said chemical difference is a difference in the atom of ametal present in said catalyst.
 5. The process of claim 1, wherein saidlibrary comprises more than 20 potential catalyst that are eachchemically different from the others.
 6. The process of claim 5, whereinsaid chemical difference is a difference in the atoms of an ancillaryligand present in said catalyst.
 7. The process of claim 5, wherein saidchemical difference is difference in the atom of a metal present in saidcatalyst.
 8. The process of claim 1, wherein said polymerizationconditions additionally comprise a temperature in the range of fromabout 0° C. to 200° C.
 9. The process of claim 1, wherein saidpolymerization conditions additionally comprise a pressure of in therange from atmospheric to 1000 psig.
 10. A process for parallelpolymerization, the process comprising providing a library of potentialmetal-ligand polymerization catalysts, and inserting the potentialcatalysts into a parallel reactor and subjecting said library topolymerization conditions, wherein (i) said library comprises more than3 potential catalyst members, (ii) said polymerization conditionsinclude contacting each of said more than 3 members with at least onemonomer that is an olefin, diolefin or acetylenically unsaturatedmonomer under different polymerization conditions, wherein thetemperature ranges from about 0° C. to about 200° C. and the pressureranges from about atmospheric to about 1000 psig, and (iii) saidparallel reactor comprises a plurality of sealed reaction vessels andeach of said more than 3 members is placed in a corresponding one ofsaid plurality of vessels.
 11. The process of claim 10, wherein saiddifferent polymerization conditions are selected from the groupconsisting of pressure, temperature, time, solvent type solvent tomonomer ratio, residence time, catalyst to activator ratio, scavengerpresence or amount, comonomer presence or amount, monomer to comonomerratio, catalyst to solvent ratio, catalyst to monomer ratio andcombinations thereof.
 12. The process of claim 11, wherein two or moreof said different polymerization conditions are varied between said morethan 3 members.
 13. The process of claim 11, wherein there are more than10 members in said library and each of said more than 10 members insubjected to different polymerization conditions.
 14. The process ofclaim 11, wherein there are more than 20 members in said library andeach of said more than 20 members is subjected to differentpolymerization conditions.
 15. The process of claim 1 wherein saidreaction vessels are located in spatially addressable regions that arephysically separated from each other.
 16. The process of claim 1 whereinsaid potential metal-ligand polymerization catalyst are activated. 17.The process of claim 1 wherein said monomer is selected from ethylene,propylene, butene, isobutylene, hexene, methylacrylate, methyl vinylether, a diene, or a combination thereof.
 18. The process of claim 10wherein said reaction vessels are located in spatially addressableregions that are physically separated from each other.
 19. The processof claim 10 wherein said potential metal-ligand polymerization catalystare activated.
 20. The process of claim 10 wherein said monomer isselected from ethylene, propylene, butene, isobutylene, hexene,methylacrylate, methyl vinyl ether, a diene, or a combination thereof.21. The process of claim 15 wherein said parallel reactor comprises atleast 10 spatially addressable vessels.
 22. The process of claim 18wherein said parallel reactor comprises at least 10 spatiallyaddressable vessels.